Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of Sepsis

Abstract

Sepsis is a life-threatening syndrome characterized by a dysregulated immune response to infection, frequently leading to multiorgan failure and high mortality. Inflammasomes-cytosolic multiprotein complexes of the innate immune system-serve as critical platforms for sensing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). Key sensors such as NLRP3, AIM2, and IFI16 initiate caspase-1 activation, IL-1β and IL-18 maturation, and gasdermin D-mediated pyroptosis. In sepsis, excessive inflammasome activation drives oxidative stress, endothelial dysfunction, immunothrombosis, and immune exhaustion. This maladaptive cascade is further aggravated by the release of DAMPs and procoagulant factors, compromising vascular integrity and immune homeostasis. Prolonged activation contributes to immunoparalysis, lymphopenia, and increased susceptibility to secondary infections. Inflammasome signaling also intersects with necroptosis and ferroptosis, amplifying systemic inflammation and tissue injury. Additionally, various pathogens exploit immune evasion strategies to modulate inflammasome responses and enhance virulence. Therapeutic interventions under investigation include selective NLRP3 inhibitors, IL-1 blockers, gasdermin D antagonists, and extracorporeal cytokine hemoadsorption. Emerging approaches emphasize biomarker-guided immunomodulation to achieve personalized therapy. While preclinical studies have shown promising results, clinical translation remains limited. Targeting inflammasomes may offer a path toward precision immunotherapy in sepsis, with potential to reduce organ dysfunction and improve survival.

Keywords: coagulation; cytokines; immunomodulation; inflammasome; pyroptosis; sepsis.

Figure 1

Inflammasome activation pathways—canonical and non-canonical. This diagram illustrates the two major pathways of inflammasome activation: the canonical route, driven by pattern recognition receptors such as NLRP3, AIM2, NLRC4, and IFI16, and the non-canonical route involving direct sensing of intracellular LPS by caspases-4/5 in humans (caspase-11 in mice). The canonical pathway requires a priming phase via NF-κB activation, leading to pro-IL-1β and pro-IL-18 expression, followed by an activation phase that triggers inflammasome assembly and caspase-1 activation. The non-canonical pathway bypasses this priming step and directly activates inflammatory caspases, leading to GSDMD cleavage, pore formation, pyroptosis, and secondary NLRP3 activation. This integrated response links microbial detection with cytokine release and regulated cell death, playing a central role in immune defense and sepsis pathogenesis.

Figure 2

Pathophysiological Consequences of Inflammasome Activation in Sepsis. This schematic illustrates the major downstream effects of inflammasome activation in sepsis, including oxidative stress (mediated by mitochondrial damage and ROS release), endothelial dysfunction (increased permeability and cytokine storm), immunothrombosis (gasdermin D-mediated pore formation and coagulation), and immunoparalysis (lymphopenia and immune checkpoint upregulation). Together, these processes drive tissue injury, multiorgan dysfunction, and immune exhaustion characteristic of advanced septic states.