Crosstalk between innate immune signaling pathways and integrated TLR, NLRP3 inflammasome, cGAS–STING, and NF-κB networks in sepsis

Abstract

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection that culminates in systemic inflammation, immune dysfunction, and multiple organ failure. Despite advances in supportive care, the molecular mechanisms underlying sepsis remain incompletely understood, largely due to the complex interplay among innate immune signaling pathways rather than the activation of individual pathways in isolation. Recent evidence indicates that extensive crosstalk between toll-like receptor (TLR), NLRP3 inflammasome, cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING), and nuclear factor-kappa B (NF-κB) signaling networks orchestrates the instigation, amplification, and resolution of inflammatory responses during sepsis. These interconnected pathways collectively regulate pathogen recognition, cytokine production, inflammasome activation, type I interferon signaling, pyroptosis, and immune cell reprogramming, while simultaneously interacting with metabolic, oxidative stress, autophagic, and programmed cell death pathways. This review comprehensively examines the molecular architecture and dynamic interactions among these signaling networks, highlighting the shared adaptor proteins, regulatory feedback loops, and signaling hubs that determine the transition from protective host defense to uncontrolled hyperinflammation and subsequent immunosuppression. We further discuss how mitochondrial dysfunction, reactive oxygen species (ROS), damage-associated molecular patterns (DAMPs), epigenetic modifications, and non-coding RNAs (ncRNAs) modulate these signaling circuits and contribute to organ-specific injury in sepsis. Emerging evidence from single-cell transcriptomics, spatial multi-omics, and systems biology methods is also explored to provide a network-level understanding of immune dysregulation and identify novel biomarkers and therapeutic targets. Finally, we summarize current and emerging therapeutic strategies aimed at modulating innate immune signaling, including inhibitors of TLRs, NLRP3 inflammasome, STING, and NF-κB, as well as combination and precision medicine approaches. By integrating canonical and emerging signaling pathways into a unified molecular framework, this review provides new insights into the pathogenesis of sepsis and highlights promising directions for the advancement of targeted immunomodulatory therapies capable of cultivating clinical outcomes.