Kupffer Cell Loss in Sepsis: Mechanisms and Therapeutic Strategies

Sepsis is a life-threatening condition caused by a dysregulated immune response to infection that causes over 350,000 deaths a year in the United States alone, yet no FDA-approved therapies exist. Kupffer Cells (KCs), the liver’s resident macrophages, are critical mediators of bacterial clearance and hepatic immune homeostasis. Their depletion during sepsis is associated with increased bacterial burden and mortality. Understanding the mechanisms driving KC loss and identifying strategies to preserve KC populations represents an important therapeutic strategy. This dissertation investigated the mechanisms of KC loss during sepsis and evaluated therapeutic strategies for KC preservation across three studies. In the first study, we demonstrated that KC loss during sepsis is mediated by PANoptosis, an inflammatory cell death program engaging pyroptotic, apoptotic, and necroptotic effectors simultaneously. Mechanistically, combinatorial exposure to free heme and bacterial PAMPs activates PLC-γ, driving cleaved gasdemin D (GSDMD) mitochondrial translocation causing mitochondrial damage and mtDNA release that activates cGAS-STING signaling, converging on PANoptotic KC death and senescence. Pharmacological inhibition of PLC-γ and enhancing heme scavenging via hemopexin treatment preserved KC populations and reduced mortality identifying heme and PLC-γ as therapeutic targets. In the second study, we showed that β-glucan induced trained immunity preserves KC populations during sepsis by suppressing NLRP3 and GSDMD expression and enhancing KC self-renewal through downregulation of cMaf and MafB. This establishes trained immunity as a viable KC preservation strategy. In the third study, we identified endothelial-derived HSPA12B as a previously unrecognized liver sinusoidal endothelial cell to KC protective signal. Endothelial-specific HSPA12B knockout exacerbated KC loss, bacterial burden, and mortality in sepsis while exosomal HSPA12B delivery suppressed PANoptotic signaling and senescence. Mechanistically, HSPA12B promotes STING degradation through upregulation of endoplasmic reticulum-associated degradation (ERAD) machinery, suppressing downstream IFN-β and ZBP1 upregulation. Pharmacological STING inhibition fully rescued KC loss in HSPA12B knockout mice, establishing STING as the primary effector of HSPA12B deficiency in driving KC PANoptosis. Together these studies define a mechanistic framework of KC loss in sepsis and identify multiple potential therapeutics for their preservation.