Complement-Mediated Inflammatory Responses in Sepsis

The complement system represents a cornerstone of innate immunity, comprising a cascade of plasma proteins that, upon activation, facilitate pathogen clearance and coordinate inflammatory signalling. In sepsis, infection‐triggered complement activation becomes dysregulated, generating effector fragments such as C3a and C5a, and culminating in formation of the membrane attack complex. These anaphylatoxins amplify vascular permeability, leukocyte recruitment and proinflammatory cytokine release, thereby contributing to endothelial injury, disseminated intravascular coagulation and organ dysfunction. Cross‐talk with toll‐like receptors and the NLRP3 inflammasome further exacerbates cytokine storm and tissue damage. While early complement activation supports microbial eradication, excessive or prolonged activity drives a maladaptive host response that underpins the systemic inflammatory response syndrome and multiple‐organ failure characteristic of severe sepsis. Understanding the temporal‐spatial dynamics of classical, lectin and alternative pathway activation has highlighted opportunities for therapeutic modulation. Selective inhibition of key enzymes or receptors within this cascade offers promise in rebalancing host defence and preventing organ injury, with potential global impact in reducing sepsis mortality and long‐term sequelae.

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Complement-Mediated Inflammatory Responses in Sepsis publication trend

The graph below shows the total number of articles in complement-mediated inflammatory responses in sepsis across all publications each year (not limited to Nature Index journals).

Technical terms

Complement system: A network of plasma proteins that, when activated via classical, lectin or alternative pathways, enhances pathogen elimination and modulates inflammation.

Anaphylatoxins (C3a, C5a): Small complement fragments that increase vascular permeability, chemotaxis and cytokine release.

Lectin pathway: Complement activation route initiated by carbohydrate‐binding proteins (e.g. mannose‐binding lectin) and MASP enzymes.

MASP-2: Mannose‐binding lectin-associated serine protease 2, a protease essential for lectin‐pathway complement activation.

Inflammasome (NLRP3): Multiprotein complex in innate immune cells that drives maturation of IL-1β and IL-18 in response to danger signals.

Acute respiratory distress syndrome (ARDS): Severe lung injury characterised by alveolar inflammation, capillary leak and hypoxaemia, often complicating sepsis.

Multiple-organ dysfunction syndrome: Progressive impairment of two or more organ systems following severe infection or injury, often mediated by excessive inflammation.

References

1. The Role of Complement System in Septic Shock. Journal of Immunology Research (2012).
2. Complement activation in severely ill patients with sepsis: no relationship with inflammation and disease severity. Critical Care (2023).
3. Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in mice. Frontiers in Immunology (2023).
4. Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases—C3 or C5 emerge together with CD14 as promising targets. Journal of Leukocyte Biology (2016).
5. Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes. Mediators of Inflammation (2016).
6. Targeting Complement Pathways in Polytrauma- and Sepsis-Induced Multiple-Organ Dysfunction. Frontiers in Immunology (2019).