β-Glucan Protects Against Sepsis-Induced Kupffer Cell Loss by Inhibiting Pyroptosis and Promoting Self-Renewal.

Abstract

Sepsis is a life-threatening condition characterised by a dysregulated host response to infection, resulting in systemic inflammation, immune dysfunction, and multi-organ failure. Kupffer cells (KCs), the largest population of tissue-resident macrophages in the body, are essential for pathogen clearance, endotoxin detoxification, and maintaining hepatic immune homeostasis during sepsis. However, sepsis induces substantial KC depletion, contributing to increased bacterial burden and mortality. In this study, we demonstrate that β-glucan treatment effectively protects against sepsis-induced KC loss and reduces circulating bacterial load. Mechanistically, β-glucan attenuates KC death by suppressing NLRP3 and gasdermin D (GSDMD)-mediated pyroptosis triggered by bacterial infections. Notably, we identify a previously unrecognised function of β-glucan in markedly enhancing KC self-renewal during sepsis through downregulation of the transcriptional repressors c-Maf and MafB, which are known to inhibit macrophage proliferation. This discovery reveals a novel mechanism of hepatic macrophage regeneration and supports β-glucan as a promising immunomodulatory therapy to preserve liver immune integrity, enhancing antibacterial defence, and reducing the risk of secondary infections in immunocompromised septic hosts.