MaltSci 麦伴科研

Appearance

Popular Reports / Immunology

This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of cytokine storms? ​

Abstract ​

Cytokine storms, marked by excessive and uncontrolled pro-inflammatory cytokine release, pose significant clinical challenges, often resulting in severe outcomes such as systemic inflammation, multi-organ failure, and death. These hyper-inflammatory responses can be triggered by various stimuli, including viral infections, autoimmune diseases, and environmental factors. Understanding the mechanisms underlying cytokine storms is critical for developing effective therapeutic strategies, particularly in life-threatening conditions like COVID-19 and severe influenza. This review explores the intricate interplay of immune cells, signaling pathways, and genetic predispositions that contribute to cytokine storm development. Key players include T cells, macrophages, and neutrophils, which activate complex signaling cascades that lead to cytokine production and inflammation. Furthermore, the review discusses various triggers of cytokine storms, highlighting the roles of viral infections, autoimmune conditions, and environmental stressors. Clinical implications and current therapeutic strategies aimed at mitigating cytokine storm effects are examined, alongside novel approaches that hold promise for future interventions. Ultimately, a comprehensive understanding of cytokine storm mechanisms may pave the way for targeted therapies that significantly improve patient outcomes in conditions characterized by this dangerous inflammatory response.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Mechanisms of Cytokine Storms
    • 2.1 Role of Immune Cells in Cytokine Production
    • 2.2 Signaling Pathways Involved in Cytokine Release
    • 2.3 Genetic Factors Influencing Cytokine Storms
  • 3 Triggers of Cytokine Storms
    • 3.1 Viral Infections and Cytokine Storms
    • 3.2 Autoimmune Conditions and Cytokine Dysregulation
    • 3.3 Environmental and Stress Factors
  • 4 Clinical Implications and Therapeutic Strategies
    • 4.1 Current Treatments for Cytokine Storms
    • 4.2 Novel Therapeutic Approaches
    • 4.3 Challenges in Managing Cytokine Storms
  • 5 Future Directions in Research
    • 5.1 Understanding Long-term Effects of Cytokine Storms
    • 5.2 Biomarkers for Early Detection
    • 5.3 Advances in Targeted Therapies
  • 6 Summary

1 Introduction ​

Cytokine storms, characterized by an excessive and uncontrolled release of pro-inflammatory cytokines, represent a critical pathophysiological phenomenon that can lead to severe clinical outcomes, including systemic inflammation, multi-organ failure, and death. This hyper-inflammatory response is typically triggered by various stimuli, including viral infections, autoimmune diseases, and environmental factors. The complexity of cytokine storms lies in their multifactorial origins and the intricate interplay between various immune cells, signaling pathways, and genetic predispositions that contribute to their development. As such, understanding the mechanisms underlying cytokine storms is paramount for the development of effective therapeutic strategies, particularly in the context of life-threatening conditions such as COVID-19, severe influenza, and certain cancers [1][2].

The significance of cytokine storms has gained increasing attention in recent years, particularly during the COVID-19 pandemic, where the phenomenon was identified as a key factor contributing to the severity of the disease and high mortality rates [3][4]. As the immune system responds to infections or other stimuli, a delicate balance between pro-inflammatory and anti-inflammatory responses is crucial for maintaining homeostasis. However, dysregulation of this balance can lead to a state of perpetual immune activation, resulting in the catastrophic consequences associated with cytokine storms [5]. The need for a comprehensive understanding of these mechanisms is underscored by the ongoing challenges in managing conditions characterized by cytokine dysregulation and the urgent demand for targeted therapeutic interventions.

Current research has begun to elucidate the various cellular and molecular mechanisms involved in cytokine storms. Key players in this process include immune cells such as neutrophils, macrophages, and T cells, which contribute to cytokine production and the subsequent inflammatory cascade [1][3]. Furthermore, specific signaling pathways, including those involving pattern recognition receptors and transcription factors, play pivotal roles in regulating cytokine release [6]. Genetic factors, such as polymorphisms in cytokine genes, also influence individual susceptibility to cytokine storms, highlighting the importance of personalized approaches in treatment [7].

This review will be organized as follows: Section 2 will delve into the mechanisms of cytokine storms, examining the roles of immune cells, signaling pathways, and genetic factors. Section 3 will identify various triggers of cytokine storms, focusing on viral infections, autoimmune conditions, and external stressors. In Section 4, we will discuss the clinical implications of cytokine storms and explore current and novel therapeutic strategies aimed at mitigating their effects. Finally, Section 5 will highlight future directions in research, emphasizing the need for a deeper understanding of long-term effects, biomarkers for early detection, and advancements in targeted therapies.

By synthesizing current research findings and integrating insights from various studies, this review aims to provide a comprehensive overview of cytokine storms, elucidating their complexities and potential intervention points for clinical practice. Ultimately, a better understanding of the mechanisms driving cytokine storms may pave the way for novel therapeutic approaches that can significantly improve patient outcomes in conditions characterized by this dangerous inflammatory response.

2 Mechanisms of Cytokine Storms ​

2.1 Role of Immune Cells in Cytokine Production ​

Cytokine storms are characterized by an uncontrolled and excessive release of proinflammatory cytokines, leading to severe immunopathological consequences, including tissue damage and organ dysfunction. Various immune cells play critical roles in the initiation and amplification of cytokine storms through complex signaling pathways and interactions.

A primary mechanism involves the activation of immune cells such as T cells, macrophages, and neutrophils, which can lead to a cascade of cytokine production. For instance, effector memory CD4+ T cells have been shown to engage CD40 and tumor necrosis factor receptor (TNFR) on myeloid cells, inducing a damaging inflammatory response. This interaction results in a broad proinflammatory program, independent of classical pattern recognition receptor (PRR) activation, indicating a novel pathway through which T cells can drive cytokine storm syndromes [8].

Neutrophils also play a significant role in the pathogenesis of cytokine storms. They are among the innate leukocytes that contribute to inflammation and can exacerbate immune responses. Neutrophils participate in the discharge of soluble mediators, and their activation can lead to a heightened inflammatory state. In various clinical scenarios, evidence has been presented showing that neutrophils can contribute to the onset of cytokine storm syndromes [3].

Moreover, endothelial cells have been identified as central orchestrators of cytokine amplification during viral infections. Studies indicate that signaling through the sphingosine-1-phosphate receptor (S1P1) on endothelial cells can modulate cytokine production and immune cell recruitment, thus influencing the severity of cytokine storms [9]. This highlights the importance of endothelial cell function in the immune response and the potential for therapeutic targeting to mitigate cytokine storm effects.

The intricate interplay between these immune cells and their signaling pathways underscores the complexity of cytokine storms. The release of proinflammatory cytokines can create a positive feedback loop, where cytokines not only induce further cytokine production but also activate cell death pathways, leading to additional inflammation and tissue damage [2]. This feedback mechanism complicates the clinical management of cytokine storms, as controlling one aspect of the immune response may not be sufficient to halt the overall process.

In summary, cytokine storms result from a multifaceted interaction of various immune cells, particularly T cells, neutrophils, and endothelial cells, each contributing to the excessive and dysregulated cytokine production. Understanding these mechanisms is crucial for developing targeted therapies aimed at mitigating the harmful effects of cytokine storms in various disease contexts.

2.2 Signaling Pathways Involved in Cytokine Release ​

Cytokine storms represent a severe systemic inflammatory response characterized by an uncontrolled release of pro-inflammatory cytokines. The mechanisms underlying cytokine storms involve various signaling pathways and cellular interactions that contribute to the exaggerated immune response. This response can lead to significant tissue damage and organ dysfunction, which are often observed in severe infections and inflammatory diseases.

One of the critical pathways implicated in cytokine storms is the Toll-like receptor (TLR) signaling pathway. TLRs are pattern recognition receptors expressed by both immune and non-immune cells, including neurons. They recognize microbial-associated molecular patterns (MAMPs) from pathogens and damage-associated molecular patterns (DAMPs) released by damaged cells. Upon recognition, TLRs activate downstream signaling cascades that result in the release of various pro-inflammatory mediators, including cytokines, chemokines, and reactive oxygen species (ROS). This process is essential for initiating an acute inflammatory response aimed at controlling infections and repairing tissue damage. However, genetic predispositions or pathogen evasion mechanisms can lead to an overactive TLR response, resulting in a cytokine storm and subsequent multi-organ dysfunction syndrome (MODS) (Kumar 2020) [10].

In addition to TLR signaling, other pathways play significant roles in the development of cytokine storms. The JAK-STAT pathway has been recognized as a crucial mediator of cytokine signaling, influencing the activation and proliferation of immune cells. Dysregulation of this pathway can lead to excessive cytokine production, contributing to the pathological features of cytokine storms (Nie et al. 2025) [11]. Furthermore, the NLRP3 inflammasome, a component of the innate immune system, is activated during cytokine storms, leading to the maturation and release of pro-inflammatory cytokines such as IL-1β and IL-18, which further amplify the inflammatory response (Karki & Kanneganti 2021) [2].

Neutrophils, as key players in the innate immune response, also contribute to the mechanisms of cytokine storms. They release a variety of cytokines and chemokines that can exacerbate inflammation. In severe infections, neutrophils can undergo a form of cell death known as pyroptosis, which is associated with the release of inflammatory mediators and can perpetuate the cytokine storm (Chan et al. 2021) [3].

Moreover, the interplay between cytokine release and cell death pathways has been observed, where certain cytokines and DAMPs can activate inflammatory cell death pathways, creating a positive feedback loop that further enhances cytokine secretion (Tang et al. 2021) [1]. This intricate network of signaling pathways and cellular interactions highlights the complexity of cytokine storms and the challenges in managing them effectively.

Overall, the mechanisms of cytokine storms are multifaceted, involving TLR signaling, the JAK-STAT pathway, the NLRP3 inflammasome, and the contributions of neutrophils and other immune cells. Understanding these mechanisms is critical for developing targeted therapies aimed at mitigating the harmful effects of cytokine storms in various clinical settings.

2.3 Genetic Factors Influencing Cytokine Storms ​

Cytokine storms are characterized by an excessive and uncontrolled release of pro-inflammatory cytokines, leading to systemic inflammation and multi-organ dysfunction. The mechanisms underlying cytokine storms are complex and multifactorial, involving a variety of cellular and molecular pathways.

One of the primary mechanisms of cytokine storms involves a positive feedback loop between cytokine release and cell death pathways. Certain cytokines, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs) can activate inflammatory cell death pathways, resulting in further cytokine secretion and exacerbation of the inflammatory response (Karki & Kanneganti, 2021) [2]. This phenomenon can lead to a cascade of immune activation that ultimately overwhelms the body's regulatory mechanisms, resulting in tissue damage and multi-organ failure.

Additionally, specific biological factors such as genetic predisposition, age, sex, and obesity can influence the severity and outcome of cytokine storms. For instance, genetic variations can affect the expression and function of key cytokines involved in the immune response, which may result in differential susceptibility to cytokine storms among individuals (Muhammad et al., 2022) [7]. Moreover, age-related changes in immune function can alter the cytokine profiles and the body’s ability to regulate inflammation, which is particularly evident in pediatric populations who may present with monogenic forms of cytokine storm syndromes (Diorio et al., 2023) [12].

The interaction between genetic factors and environmental triggers, such as infections, is also critical in the pathogenesis of cytokine storms. For example, the influenza virus has been shown to induce cytokine storms through mechanisms that include the activation of innate immune responses and the subsequent release of pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) (Gu et al., 2021) [13]. These cytokines play a significant role in cell-to-cell communication and are essential for viral clearance; however, their excessive production can lead to severe immune pathology.

In summary, the mechanisms of cytokine storms involve a complex interplay of cellular responses, genetic predispositions, and environmental factors. The understanding of these mechanisms is crucial for developing targeted therapeutic strategies aimed at mitigating the effects of cytokine storms in various clinical settings.

3 Triggers of Cytokine Storms ​

3.1 Viral Infections and Cytokine Storms ​

Cytokine storms are characterized by an excessive and uncontrolled release of pro-inflammatory cytokines, leading to systemic inflammation and potentially severe clinical outcomes. Various mechanisms can trigger cytokine storms, particularly in the context of viral infections. The underlying processes involve multiple immune cells and signaling pathways that result in a dysregulated immune response.

One of the primary triggers of cytokine storms during viral infections is the overactivation of the innate immune system. In response to viral pathogens, the immune system is designed to produce cytokines and chemokines to facilitate an antiviral response. However, in cases of severe infection, this response can become exaggerated. For instance, during respiratory viral infections, such as those caused by SARS-CoV-2, H1N1 influenza, and others, the cytokine storm plays a critical role in the pathogenesis of respiratory diseases. This can lead to complications such as alveolar edema and hypoxia, significantly impacting clinical outcomes and mortality rates (Murdaca et al., 2021) [14].

The involvement of specific immune cells, such as neutrophils, macrophages, and T cells, is also crucial in the development of cytokine storms. Neutrophils, for example, are mediators of inflammation that can exacerbate the inflammatory response if not properly regulated. They contribute to the pathogenesis of cytokine storms by releasing various cytokines that promote inflammation, thus perpetuating the cycle of immune activation (Chan et al., 2021) [3]. Similarly, CD8+ T cells can initiate a cytokine storm in response to viral infections by producing cytokines such as gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), which can further amplify the inflammatory response (Walsh et al., 2014) [15].

The cytokine storm mechanism varies across different viral infections. For example, during influenza virus infections, the storm is often characterized by elevated levels of pro-inflammatory cytokines and chemokines, leading to hypercytokinemia, which is associated with acute respiratory distress syndrome (ARDS) and high mortality rates (Wei et al., 2022) [16]. The interplay between various cytokines and their receptors can create a feedback loop that exacerbates inflammation and tissue damage.

Furthermore, certain factors such as age, sex, and underlying health conditions can influence the severity of cytokine storms. For instance, the response to influenza virus-induced cytokine storms can vary based on biological differences among individuals, which affects the overall immune response (Gu et al., 2021) [13].

In summary, cytokine storms triggered by viral infections involve complex interactions among immune cells and cytokines, leading to an exaggerated inflammatory response. Understanding these mechanisms is critical for developing targeted therapies to mitigate the harmful effects of cytokine storms and improve clinical outcomes in patients suffering from severe viral infections.

3.2 Autoimmune Conditions and Cytokine Dysregulation ​

Cytokine storms represent a pathological state characterized by excessive and uncontrolled release of pro-inflammatory cytokines, leading to systemic inflammation and multi-organ dysfunction. The mechanisms underlying cytokine storms are complex and multifaceted, involving a variety of cellular interactions and signaling pathways.

One of the primary triggers of cytokine storms is an overactive immune response, which can occur in the context of acute systemic infections. This phenomenon is often initiated by pathogenic microorganisms that activate the immune system excessively, resulting in a surge of circulating cytokines. Various immune cells, including T cells, macrophages, and neutrophils, play critical roles in the induction and progression of cytokine storms. For instance, effector memory CD4+ T cells have been shown to engage with myeloid cells through CD40 and tumor necrosis factor receptor (TNFR) interactions, which leads to a broad pro-inflammatory response in the innate immune system, independent of classical pattern recognition receptor (PRR) activation (McDaniel et al., 2022) [8].

Moreover, cytokine storms are not limited to infectious diseases; they can also arise in autoimmune conditions. In autoimmune diseases, there is often a persistent imbalance between pro-inflammatory and anti-inflammatory cytokines, which contributes to chronic inflammation. The action of cytokines such as interleukin (IL)-12, IL-17, IL-23, and IL-27 is central to the pathogenesis of these disorders, as they promote inflammatory signaling cascades that exacerbate tissue damage and dysregulation of immune responses (Paunovic et al., 2008) [17].

In addition to infections and autoimmune conditions, cytokine storms can be triggered by various non-infectious stimuli, including therapeutic interventions such as cancer immunotherapy. The release of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) can activate inflammatory pathways that lead to cytokine storm phenomena. This excessive cytokine release creates a positive feedback loop, where cytokines further stimulate inflammatory cell death pathways, resulting in additional cytokine secretion and amplifying the inflammatory response (Karki & Kanneganti, 2021) [2].

The dysregulation of cytokine production can also result from a failure to shift from innate to adaptive immune responses, as observed in severe COVID-19 cases. In such scenarios, the initial viral infection disrupts normal signaling pathways, leading to a hyper-inflammatory state characterized by elevated levels of cytokines such as IL-6, IL-1β, and TNF-α, which further exacerbate tissue damage and contribute to the clinical severity of the disease (Hiti et al., 2025) [18].

In summary, cytokine storms are driven by a combination of factors, including acute infections, autoimmune dysregulation, and therapeutic interventions. The involvement of various immune cells and the interplay of different cytokines highlight the complexity of these events, necessitating targeted therapeutic strategies to manage and mitigate the detrimental effects associated with cytokine storms.

3.3 Environmental and Stress Factors ​

Cytokine storms represent a complex pathophysiological state characterized by an overactive immune response, resulting in excessive release of pro-inflammatory cytokines. This phenomenon can be triggered by various environmental and stress factors, leading to significant tissue damage and multi-organ failure.

The mechanisms behind cytokine storms are multifaceted, involving both host and pathogen interactions. Cytokine storms can occur in response to acute systemic infections, where an exaggerated immune response is activated. For instance, during infections with influenza viruses, the cytokine storm is driven by the host's immune response to viral antigens, which can result in severe immunopathology due to the overproduction of cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) [13]. Factors such as age, sex, and underlying health conditions (e.g., obesity) can modulate the severity and characteristics of the cytokine storm, indicating that individual biological differences significantly influence the immune response [13].

In addition to infectious triggers, non-infectious factors can also precipitate cytokine storms. For example, severe inflammatory responses can arise from autoimmune conditions, certain cancers, or even adverse reactions to medications. Neutrophils, macrophages, and other innate immune cells play crucial roles in this process, as they release a variety of cytokines that can further amplify the inflammatory response [3]. The interplay between these immune cells and the cytokines they produce can create a feedback loop, exacerbating the initial immune response and leading to a full-blown cytokine storm.

Environmental stressors, such as exposure to toxins or allergens, can also trigger cytokine storms by activating pattern recognition receptors (PRRs) on immune cells, which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This activation can lead to a cascade of cytokine production, contributing to the hyper-inflammatory state characteristic of cytokine storms [7].

Moreover, the involvement of epigenetic modifications has been highlighted as a potential mechanism influencing cytokine storm responses. Genetic variations and epigenetic changes can alter the expression and function of cytokines, thereby impacting the overall immune response during infections like COVID-19 [7]. Understanding these mechanisms is crucial for developing targeted therapies aimed at mitigating the effects of cytokine storms, especially in conditions like COVID-19, where they have been linked to severe disease outcomes [4].

In summary, the mechanisms of cytokine storms are triggered by a combination of infectious agents, environmental stressors, and individual biological factors, leading to a dysregulated immune response characterized by excessive cytokine production and systemic inflammation. Addressing these underlying mechanisms is essential for effective therapeutic interventions to prevent or manage cytokine storm syndromes.

4 Clinical Implications and Therapeutic Strategies ​

4.1 Current Treatments for Cytokine Storms ​

Cytokine storms, characterized by excessive and uncontrolled release of pro-inflammatory cytokines, are implicated in severe systemic inflammatory responses leading to conditions such as acute respiratory distress syndrome (ARDS), hemophagocytic lymphohistiocytosis (HLH), and multiple organ failure. The pathogenesis of cytokine storms involves complex interactions between various immune cells and signaling pathways, which can vary depending on the underlying cause of the storm.

The mechanisms underlying cytokine storms include a positive feedback loop between cytokine release and inflammatory cell death pathways. For instance, certain cytokines, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs) can activate inflammatory cell death, which in turn leads to further cytokine secretion, creating a vicious cycle of inflammation and tissue damage (Karki and Kanneganti, 2021) [2]. Moreover, specific signaling pathways, such as the JAK-STAT pathway, Toll-like receptors, and the NLRP3 inflammasome, have been recognized as key players in the pathogenesis of cytokine storms (Nie et al., 2025) [11].

Clinical implications of cytokine storms are profound, as they can result in severe morbidity and mortality. The excessive immune response can lead to rapid progression of immune-mediated damage to healthy tissues, culminating in multi-organ failure. Therefore, prompt recognition and intervention are critical to mitigate the damage caused by cytokine storms (Weaver, 2018) [19].

Current treatments for cytokine storms focus on dampening the hyper-inflammatory response and restoring immune homeostasis. Therapeutic strategies include the use of corticosteroids, which have been recognized for their ability to reduce inflammation and improve outcomes in patients experiencing cytokine storms, particularly in cases associated with COVID-19 (Ye et al., 2020) [4]. However, the effectiveness of steroid therapy can be limited, necessitating the exploration of alternative or adjunctive therapies.

Emerging therapeutic approaches involve targeting specific pathways involved in the cytokine storm response. For instance, therapies that modulate macrophage function have gained attention, as dysfunctional macrophages play a significant role in the development of cytokine storms. Nanomedicine-based therapies targeting macrophages have shown promise in reducing cytokine production and improving outcomes in animal models of pro-inflammatory diseases (Liu et al., 2020) [20]. Additionally, novel agents targeting specific cytokines or signaling pathways are under investigation, aiming to provide more effective interventions for managing cytokine storms (Potapov et al., 2022) [21].

In summary, cytokine storms arise from a complex interplay of immune mechanisms that lead to excessive inflammation and tissue damage. Understanding these mechanisms is crucial for developing effective therapeutic strategies to mitigate the impact of cytokine storms and improve patient outcomes.

4.2 Novel Therapeutic Approaches ​

Cytokine storms (CS) represent a severe systemic inflammatory response characterized by the excessive activation of immune cells and significantly elevated levels of circulating cytokines. This pathological process is associated with life-threatening conditions, including fulminant myocarditis, acute respiratory distress syndrome (ARDS), and cytokine release syndrome (CRS) related to therapies such as chimeric antigen receptor-modified T (CAR-T) cell therapy [11]. The mechanisms underlying cytokine storms involve complex interactions between various signaling pathways and cellular responses.

One of the key mechanisms is the positive feedback loop between cytokine release and inflammatory cell death pathways. Certain cytokines, along with pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), can activate inflammatory cell death, which in turn leads to further cytokine secretion [2]. This dysregulated immune response can result in a cascade of events that amplify the inflammatory response, leading to significant tissue damage and organ failure [1].

Specific signaling pathways have been implicated in the pathogenesis of cytokine storms. For instance, the JAK-STAT pathway, Toll-like receptors, and the NLRP3 inflammasome are critical components that mediate the immune response and cytokine production [11]. Dysregulation in these pathways can contribute to the hyperinflammatory state observed in cytokine storms. Furthermore, neutrophils and other innate immune cells play significant roles in the development and progression of cytokine storms, as they can release a variety of inflammatory mediators that exacerbate the immune response [3].

From a clinical perspective, the management of cytokine storms typically requires a multidisciplinary approach. This includes the removal of abnormal inflammatory or immune system activation, preservation of vital organ function, treatment of the underlying disease, and supportive care [11]. Novel therapeutic strategies are being explored to mitigate the effects of cytokine storms. For example, targeting specific signaling pathways, such as those involving the JAK-STAT pathway or utilizing nanotechnology-based therapeutics to reduce cytokine production, has shown promise [22].

Recent advances in understanding the pathophysiology of cytokine storms have led to the identification of potential therapeutic targets, including the activation of nuclear factor erythroid 2-related factor 2 (NRF2), which may help in mitigating inflammation and preventing the onset of cytokine storms [23]. The development of biomarker panels for rapid diagnosis and differentiation of cytokine storm syndromes also holds clinical utility, facilitating timely interventions that could limit immune-mediated damage to healthy tissues [19].

In summary, the mechanisms of cytokine storms involve intricate interactions between various immune cells and signaling pathways that lead to a hyperinflammatory state. Understanding these mechanisms is crucial for developing effective therapeutic strategies aimed at alleviating the detrimental effects of cytokine storms and improving patient outcomes.

4.3 Challenges in Managing Cytokine Storms ​

Cytokine storms (CS) represent a severe systemic inflammatory syndrome characterized by an uncontrolled release of proinflammatory cytokines, leading to tissue damage and multiorgan dysfunction. The underlying mechanisms of cytokine storms are complex and multifactorial, involving both innate and adaptive immune responses.

The pathogenesis of cytokine storms typically begins with an overactivation of the immune system, often triggered by infections, autoimmune diseases, or therapeutic interventions. In the context of infectious diseases, an acute systemic infection can lead to the excessive activation of immune cells, resulting in a rapid increase in circulating cytokines. This phenomenon is particularly evident in severe cases of viral infections, such as COVID-19, where it has been shown that the severe deterioration of patients correlates closely with the onset of a cytokine storm (Ye et al. 2020) [4].

Recent studies have highlighted several critical pathways involved in the development of cytokine storms. For instance, the JAK-STAT signaling pathway, Toll-like receptors, and the NLRP3 inflammasome have been identified as significant contributors to the excessive immune response seen in cytokine storms. These pathways facilitate the activation of immune cells, leading to the release of proinflammatory cytokines and further perpetuating the inflammatory cycle (Nie et al. 2025) [11]. Additionally, neutrophils play a pivotal role in this process by mediating inflammation and contributing to tissue damage through the release of reactive oxygen species and proteolytic enzymes (Chan et al. 2021) [3].

The clinical implications of cytokine storms are profound, as they can lead to life-threatening conditions such as acute respiratory distress syndrome (ARDS), fulminant myocarditis, and systemic inflammatory response syndrome (SIRS). These complications arise from the dysregulated immune response that not only targets pathogens but also causes significant damage to host tissues (Murdaca et al. 2021) [14]. The rapid progression of immune-mediated damage underscores the urgency for prompt recognition and intervention in patients exhibiting signs of cytokine storms.

Managing cytokine storms presents significant challenges. The clinical heterogeneity of cytokine storm syndromes complicates diagnosis and treatment. While corticosteroids are commonly used to mitigate the inflammatory response, their efficacy can be limited, and the timing of administration is crucial for optimizing outcomes (Armstrong et al. 2024) [5]. Moreover, the high mortality rates associated with cytokine storms necessitate a multidisciplinary approach that includes not only the suppression of abnormal immune activation but also the preservation of vital organ function and the treatment of underlying diseases (Nie et al. 2025) [11].

Emerging therapeutic strategies targeting specific signaling pathways involved in cytokine storms, such as inhibitors of the JAK-STAT pathway and other inflammatory mediators, are currently under investigation. These novel therapies aim to alleviate tissue damage while promoting pathogen clearance, thereby improving clinical outcomes (Tang et al. 2021) [1]. However, the complexity of cytokine storm pathophysiology continues to pose significant obstacles to effective treatment, highlighting the need for ongoing research to develop more precise and effective therapeutic interventions.

In summary, the mechanisms of cytokine storms involve a complex interplay of immune activation pathways leading to excessive cytokine production and tissue damage. The clinical implications are severe, necessitating rapid diagnosis and intervention, while the challenges in managing these syndromes underscore the need for targeted therapeutic strategies.

5 Future Directions in Research ​

5.1 Understanding Long-term Effects of Cytokine Storms ​

Cytokine storms represent an acute pathophysiological state characterized by an overwhelming release of pro-inflammatory cytokines, which can lead to systemic inflammatory responses and multi-organ failure. The mechanisms underlying cytokine storms are multifaceted and involve a complex interplay between various immune cells, cytokines, and cellular signaling pathways.

Cytokine storms typically arise following an overactive immune response to infections, such as those caused by viruses or bacteria, as well as in certain autoimmune diseases. The initial trigger often involves pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) that activate immune cells. This activation leads to the release of pro-inflammatory cytokines, which further stimulate immune cell recruitment and activation, creating a positive feedback loop that exacerbates the inflammatory response [2].

Recent studies highlight the role of specific immune cells, particularly neutrophils, in the pathogenesis of cytokine storms. Neutrophils can contribute to the inflammatory milieu through the release of reactive oxygen species (ROS) and cytokines, which can promote tissue damage and enhance the inflammatory response [3]. Moreover, certain cytokines are known to induce inflammatory cell death, which further propagates cytokine release and amplifies the storm [2].

Another critical aspect of cytokine storm mechanisms involves the dysregulation of immune homeostasis. In a normal immune response, there is a balance between pro-inflammatory and anti-inflammatory signals that ensure tissue repair and resolution of inflammation. However, in cytokine storms, this balance is disrupted, leading to sustained inflammation and tissue injury [1]. Factors such as age, sex, and underlying health conditions can also influence the severity and outcomes of cytokine storms, as these factors may alter immune responses and cytokine profiles [13].

Long-term effects of cytokine storms can include persistent inflammation, tissue damage, and even chronic diseases. For instance, patients recovering from severe COVID-19 often exhibit prolonged symptoms associated with immune dysregulation, which may stem from the cytokine storm experienced during acute infection [24]. Understanding these long-term effects is crucial for developing therapeutic strategies aimed at mitigating the consequences of cytokine storms.

Future research directions should focus on elucidating the precise molecular mechanisms that lead to cytokine storm initiation and progression. Investigating the role of epigenetic modifications in cytokine gene expression during storms may provide insights into individual variability in response and recovery [7]. Additionally, exploring potential therapeutic targets, such as nuclear factor erythroid 2-related factor 2 (NRF2), which may help regulate inflammation and oxidative stress during cytokine storms, could lead to novel treatment approaches [23].

In summary, the mechanisms of cytokine storms are complex and involve a cascade of immune responses characterized by excessive cytokine production and dysregulated immune homeostasis. Understanding these mechanisms is essential for developing effective therapeutic interventions and addressing the long-term impacts of cytokine storms on health.

5.2 Biomarkers for Early Detection ​

Cytokine storms are characterized by an excessive release of pro-inflammatory cytokines, leading to severe systemic inflammation and potentially life-threatening multi-organ failure. The mechanisms underlying cytokine storms are complex and multifaceted, involving various cellular and molecular pathways.

One significant mechanism involves a positive feedback loop between cytokine release and inflammatory cell death pathways. Certain cytokines, along with pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), can activate inflammatory cell death, which in turn leads to further cytokine secretion. This phenomenon highlights the interconnectedness of cytokine signaling and cell death in the progression of cytokine storms [2].

Neutrophils, macrophages, and other innate immune cells play crucial roles in the pathogenesis of cytokine storms. For instance, neutrophils can mediate inflammation and contribute to the exacerbation of inflammatory responses. Their activation and subsequent cytokine production can significantly amplify the inflammatory response, further driving the cytokine storm [3]. Additionally, endothelial cells have been identified as central orchestrators of cytokine amplification during infections, particularly viral infections, by regulating cytokine release and immune cell infiltration [9].

The release of cell-free chromatin particles from dying cells has also been proposed as a novel mechanism triggering cytokine storms. These particles can integrate into the genomes of healthy cells, leading to DNA breaks and subsequent inflammatory responses. This cascade of events results in a vicious cycle of cell death and hyper-inflammation, potentially explaining the high mortality rates associated with severe infections such as COVID-19 [25].

In terms of future research directions, there is a growing interest in identifying biomarkers for the early detection of cytokine storms. Current studies suggest that profiling cytokines and chemokines can aid in differentiating between various cytokine storm syndromes, which is crucial for timely and effective therapeutic interventions [26]. For example, specific serum biomarkers like S100A12 and interleukin-18 have shown promise in distinguishing between primary hemophagocytic lymphohistiocytosis (HLH) and other related conditions, indicating their potential utility in clinical diagnostics [26].

The development of point-of-care testing (POCT) for cytokines is another promising avenue, as it could facilitate rapid monitoring and management of cytokine storms, particularly in acute settings such as sepsis and COVID-19 [27]. Moreover, therapeutic strategies targeting specific cytokines or pathways involved in cytokine storms are under investigation, with the goal of mitigating their detrimental effects [1].

In summary, the mechanisms of cytokine storms involve intricate interactions between various immune cells and signaling pathways, with significant implications for understanding and managing these critical conditions. Future research focused on biomarker identification and therapeutic interventions holds the potential to improve outcomes for patients experiencing cytokine storms.

5.3 Advances in Targeted Therapies ​

Cytokine storms, characterized by an excessive and uncontrolled release of pro-inflammatory cytokines, represent a severe systemic inflammatory response that can lead to significant morbidity and mortality. The mechanisms underlying cytokine storms are complex and multifaceted, involving various cellular and molecular pathways.

One of the primary mechanisms involves the activation of immune cells, such as macrophages and neutrophils, which release large amounts of cytokines in response to pathogens or other stimuli. For instance, neutrophils contribute to the pathogenesis of cytokine storms by mediating inflammation and promoting homeostasis following pathological inflammation, but they can also exacerbate the inflammatory response, leading to immunopathological events [3]. Additionally, the positive feedback loop between cytokine release and cell death pathways has been noted, where certain cytokines can activate inflammatory cell death, further exacerbating cytokine secretion [2].

The role of specific signaling pathways has also been highlighted in the pathogenesis of cytokine storms. For example, the JAK-STAT pathway, Toll-like receptors, and the NLRP3 inflammasome have been implicated in the excessive activation of immune responses [11]. Moreover, the dysregulation of macrophage function plays a critical role, as dysfunctional macrophages can lead to the excessive production of pro-inflammatory cytokines [20].

Research into targeted therapies for cytokine storms is evolving, with several promising strategies being explored. These include therapies that target specific cytokines, signaling pathways, or immune cell functions. For instance, interventions targeting the NRF2 pathway have been proposed as a means to mitigate inflammation and, consequently, cytokine storms [23]. Additionally, nanomedicine approaches that focus on modulating macrophage dysfunction have shown potential in reducing cytokine production and improving outcomes in severe infections [22].

Future directions in research should focus on a deeper understanding of the molecular mechanisms driving cytokine storms, as well as the development of more effective therapeutic strategies. This includes investigating the interplay between various cytokines and their receptors, the role of genetic and epigenetic factors in individual responses to cytokine storms, and the potential for combination therapies that can target multiple pathways simultaneously. The integration of advanced technologies, such as multi-omics profiling, could facilitate the identification of novel biomarkers and therapeutic targets, ultimately leading to more personalized treatment approaches for patients experiencing cytokine storms [1].

Overall, the complexities of cytokine storms necessitate a multidisciplinary approach to research and treatment, incorporating insights from immunology, molecular biology, and therapeutic development to enhance patient outcomes and address the challenges posed by this severe inflammatory response.

6 Conclusion ​

Cytokine storms are a complex and critical pathophysiological phenomenon characterized by an excessive and uncontrolled release of pro-inflammatory cytokines, leading to severe clinical consequences such as systemic inflammation and multi-organ failure. The review highlights the multifaceted mechanisms driving cytokine storms, which include the activation of various immune cells such as T cells, macrophages, and neutrophils, as well as intricate signaling pathways like the Toll-like receptor (TLR) and JAK-STAT pathways. These mechanisms create a positive feedback loop that exacerbates inflammation and tissue damage. Current research emphasizes the need for targeted therapeutic strategies to mitigate the effects of cytokine storms, particularly in severe infections and autoimmune conditions. Emerging treatments, including the use of corticosteroids and novel agents targeting specific cytokines or pathways, show promise in managing these syndromes. However, challenges remain in effectively diagnosing and treating cytokine storms due to their clinical heterogeneity. Future research should focus on identifying biomarkers for early detection, understanding the long-term effects of cytokine storms, and advancing targeted therapies to improve patient outcomes. A comprehensive understanding of the mechanisms underlying cytokine storms is essential for developing effective interventions and ultimately reducing the morbidity and mortality associated with these severe inflammatory responses.

References ​

  • [1] Xi-Dian Tang;Tian-Tian Ji;Jia-Rui Dong;Hao Feng;Feng-Qiang Chen;Xi Chen;Hui-Ying Zhao;De-Kun Chen;Wen-Tao Ma. Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases.. International journal of molecular sciences(IF=4.9). 2021. PMID:34884813. DOI: 10.3390/ijms222313009.
  • [2] Rajendra Karki;Thirumala-Devi Kanneganti. The 'cytokine storm': molecular mechanisms and therapeutic prospects.. Trends in immunology(IF=13.9). 2021. PMID:34217595. DOI: 10.1016/j.it.2021.06.001.
  • [3] Lily Chan;Negar Karimi;Solmaz Morovati;Kasra Alizadeh;Julia E Kakish;Sierra Vanderkamp;Fatemeh Fazel;Christina Napoleoni;Kimia Alizadeh;Yeganeh Mehrani;Jessica A Minott;Byram W Bridle;Khalil Karimi. The Roles of Neutrophils in Cytokine Storms.. Viruses(IF=3.5). 2021. PMID:34835125. DOI: 10.3390/v13112318.
  • [4] Qing Ye;Bili Wang;Jianhua Mao. The pathogenesis and treatment of the `Cytokine Storm' in COVID-19.. The Journal of infection(IF=11.9). 2020. PMID:32283152. DOI: 10.1016/j.jinf.2020.03.037.
  • [5] Amy Armstrong;Yuting Tang;Neelam Mukherjee;Nu Zhang;Gang Huang. Into the storm: the imbalance in the yin-yang immune response as the commonality of cytokine storm syndromes.. Frontiers in immunology(IF=5.9). 2024. PMID:39318634. DOI: 10.3389/fimmu.2024.1448201.
  • [6] Maria Chiara Pelle;Isabella Zaffina;Michele Provenzano;Giovenale Moirano;Franco Arturi. COVID-19 and diabetes-Two giants colliding: From pathophysiology to management.. Frontiers in endocrinology(IF=4.6). 2022. PMID:36060943. DOI: 10.3389/fendo.2022.974540.
  • [7] Aliyu Muhammad;Gilead Ebiegberi Forcados;Hadiza Sani;Uche Samuel Ndidi;Auwal Adamu;Babangida Sanusi Katsayal;Idris Zubairu Sadiq;Yakubu Saddeeq Abubakar;Ibrahim Sulaiman;Ibrahim Babangida Abubakar;Abdurrahman Pharmacy Yusuf;Ibrahim Malami;Sani Ibrahim;Murtala Bello Abubakar. Epigenetic modifications associated with genes implicated in cytokine storm: The potential biotherapeutic effects of vitamins and minerals in COVID-19.. Journal of food biochemistry(IF=4.2). 2022. PMID:35060145. DOI: 10.1111/jfbc.14079.
  • [8] Margaret M McDaniel;Amanpreet Singh Chawla;Aakanksha Jain;Hannah E Meibers;Irene Saha;Yajing Gao;Viral Jain;Krishna Roskin;Sing Sing Way;Chandrashekhar Pasare. Effector memory CD4+ T cells induce damaging innate inflammation and autoimmune pathology by engaging CD40 and TNFR on myeloid cells.. Science immunology(IF=16.3). 2022. PMID:35061504. DOI: 10.1126/sciimmunol.abk0182.
  • [9] John R Teijaro;Kevin B Walsh;Stuart Cahalan;Daniel M Fremgen;Edward Roberts;Fiona Scott;Esther Martinborough;Robert Peach;Michael B A Oldstone;Hugh Rosen. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection.. Cell(IF=42.5). 2011. PMID:21925319. DOI: 10.1016/j.cell.2011.08.015.
  • [10] V Kumar. Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets.. International immunopharmacology(IF=4.7). 2020. PMID:33075714. DOI: 10.1016/j.intimp.2020.107087.
  • [11] Jiali Nie;Ling Zhou;Weiwei Tian;Xiansheng Liu;Liping Yang;Xingcheng Yang;Yicheng Zhang;Shuang Wei;Dao Wen Wang;Jia Wei. Deep insight into cytokine storm: from pathogenesis to treatment.. Signal transduction and targeted therapy(IF=52.7). 2025. PMID:40234407. DOI: 10.1038/s41392-025-02178-y.
  • [12] Caroline Diorio;David T Teachey;Scott W Canna. Cytokine Storm Syndromes in Pediatric Patients.. The journal of allergy and clinical immunology. In practice(IF=6.6). 2023. PMID:36990432. DOI: 10.1016/j.jaip.2023.03.033.
  • [13] Yinuo Gu;Xu Zuo;Siyu Zhang;Zhuoer Ouyang;Shengyu Jiang;Fang Wang;Guoqiang Wang. The Mechanism behind Influenza Virus Cytokine Storm.. Viruses(IF=3.5). 2021. PMID:34372568. DOI: 10.3390/v13071362.
  • [14] Giuseppe Murdaca;Francesca Paladin;Alessandro Tonacci;Stefania Isola;Alessandro Allegra;Sebastiano Gangemi. The Potential Role of Cytokine Storm Pathway in the Clinical Course of Viral Respiratory Pandemic.. Biomedicines(IF=3.9). 2021. PMID:34829918. DOI: 10.3390/biomedicines9111688.
  • [15] Kevin B Walsh;John R Teijaro;Linda G Brock;Daniel M Fremgen;Peter L Collins;Hugh Rosen;Michael B A Oldstone. Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy.. Journal of virology(IF=3.8). 2014. PMID:24672024. DOI: 10.1128/JVI.00464-14.
  • [16] Fanhua Wei;Chengjiang Gao;Yujiong Wang. The role of influenza A virus-induced hypercytokinemia.. Critical reviews in microbiology(IF=5.1). 2022. PMID:34353210. DOI: 10.1080/1040841X.2021.1960482.
  • [17] V Paunovic;H P Carroll;K Vandenbroeck;M Gadina. Signalling, inflammation and arthritis: crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity.. Rheumatology (Oxford, England)(IF=4.4). 2008. PMID:18238793. DOI: 10.1093/rheumatology/kem352.
  • [18] Luka Hiti;Tijana Markovič;Mitja Lainscak;Jerneja Farkaš Lainščak;Emil Pal;Irena Mlinarič-Raščan. The immunopathogenesis of a cytokine storm: The key mechanisms underlying severe COVID-19.. Cytokine & growth factor reviews(IF=11.8). 2025. PMID:39884914. DOI: 10.1016/j.cytogfr.2024.12.003.
  • [19] L K Weaver. Combining multiple biomarkers differentiates between active SJIA, SJIA-MAS and EBV-HLH.. Clinical and experimental immunology(IF=3.8). 2018. PMID:28975999. DOI: 10.1111/cei.13063.
  • [20] Jingping Liu;Meihua Wan;Christopher J Lyon;Tony Y Hu. Nanomedicine therapies modulating Macrophage Dysfunction: a potential strategy to attenuate Cytokine Storms in severe infections.. Theranostics(IF=13.3). 2020. PMID:32863947. DOI: 10.7150/thno.47982.
  • [21] Ilya Potapov;Thirumala-Devi Kanneganti;Antonio Del Sol. Fostering experimental and computational synergy to modulate hyperinflammation.. Trends in immunology(IF=13.9). 2022. PMID:34844849. DOI: 10.1016/j.it.2021.11.004.
  • [22] Mohd Ahmar Rauf;Maryam Nisar;Hosam Abdelhady;Navnath Gavande;Arun K Iyer. Nanomedicine approaches to reduce cytokine storms in severe infections.. Drug discovery today(IF=7.5). 2022. PMID:36099962. DOI: 10.1016/j.drudis.2022.103355.
  • [23] Zihang Liu;Panpan Deng;Shengnan Liu;Yiying Bian;Yuanyuan Xu;Qiang Zhang;Huihui Wang;Jingbo Pi. Is Nuclear Factor Erythroid 2-Related Factor 2 a Target for the Intervention of Cytokine Storms?. Antioxidants (Basel, Switzerland)(IF=6.6). 2023. PMID:36671034. DOI: 10.3390/antiox12010172.
  • [24] Reza Afrisham;Yasaman Jadidi;Maryam Davoudi;Kiana Moayedi;Omid Soliemanifar;Chrysovalantou Eleni Xirouchaki;Damoon Ashtary-Larky;Shadisadat Seyyedebrahimi;Shaban Alizadeh. Gastrointestinal, Liver, Pancreas, Oral and Psychological Long-term Symptoms of COVID-19 After Recovery: A Review.. Mini reviews in medicinal chemistry(IF=3.3). 2023. PMID:36397624. DOI: 10.2174/1389557523666221116154907.
  • [25] Snehal Shabrish;Indraneel Mittra. Cytokine Storm as a Cellular Response to dsDNA Breaks: A New Proposal.. Frontiers in immunology(IF=5.9). 2021. PMID:33597956. DOI: 10.3389/fimmu.2021.622738.
  • [26] Christoph Kessel;Ndate Fall;Alexei Grom;Wilco de Jager;Sebastiaan Vastert;Raffaele Strippoli;Claudia Bracaglia;Erik Sundberg;AnnaCarin Horne;Stephan Ehl;Sandra Ammann;Carine Wouters;Kai Lehmberg;Fabrizio De Benedetti;Carolin Park;Claas Hinze;Helmut Wittkowski;Katharina Kessel;Karin Beutel;Dirk Foell;Dirk Holzinger. Definition and validation of serum biomarkers for optimal differentiation of hyperferritinaemic cytokine storm conditions in children: a retrospective cohort study.. The Lancet. Rheumatology(IF=16.4). 2021. PMID:38287622. DOI: 10.1016/S2665-9913(21)00115-6.
  • [27] Guozhen Liu;Cheng Jiang;Xiaoting Lin;Yang Yang. Point-of-care detection of cytokines in cytokine storm management and beyond: Significance and challenges.. View (Beijing, China)(IF=8.5). 2021. PMID:34766163. DOI: 10.1002/VIW.20210003.

MaltSci Intelligent Research Services ​

Search for more papers on MaltSci.com ​

cytokine storm · immune cells · signaling pathways · therapeutic strategies · viral infections

© 2025 MaltSci