IL-37 and IL-38 in sepsis: immune-metabolic rheostats in a dynamic inflammatory continuum

Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection, characterised by dynamic and overlapping phases of hyperinflammation and immune suppression. Despite advances in critical care, effective immunomodulatory therapies remain lacking, reflecting an incomplete understanding of its complex immunopathology. Central to sepsis progression is the cytokine storm, a transient but dominant inflammatory surge that contributes to endothelial injury, microvascular dysfunction, and multi-organ failure, followed in some patients by compensatory immunosuppression. Within this evolving immunological landscape, IL-37 and IL-38 have emerged as key members of the IL-1 cytokine family with context-dependent immunoregulatory functions. IL-37 broadly suppresses NF-κB- and MAPK-mediated inflammatory signalling and reprogrammes immunometabolism via mTOR inhibition, thereby attenuating pro-inflammatory cytokine production and modulating innate immune cell activity. IL-38, in contrast, exerts protective effects through regulation of inflammasome activation, promotion of regulatory T (Treg) cell responses, and suppression of effector T cell differentiation, collectively contributing to improved bacterial clearance and reduced systemic inflammation. Although both cytokines are elevated in sepsis and generally associated with disease severity, experimental evidence suggests that they function as endogenous brakes that limit excessive immune activation. However, clinical data remain heterogeneous, particularly regarding IL-10 regulation and stage-specific effects, highlighting context-dependent and compartment-specific actions. This mini-review synthesises current evidence on IL-37 and IL-38 in sepsis, emphasising their roles as integrated immunometabolic regulators rather than phase-specific mediators. We further discuss translational limitations and propose future directions centred on longitudinal immune profiling and precision immunomodulation.