Resistin immunomodulation in healthy and septic patients

Abstract

Sepsis is a major healthcare challenge worldwide with no effective therapies. Sepsis pathogenesis involves immune dysregulation, however, the underlying mechanisms of inflammation that are protective or pathogenic in sepsis remain unclear. Human resistin is an immune cell-derived protein that is elevated in sepsis. Employing human resistin-expressing transgenic mouse we identified a protective role for resistin in preventing fatal LPS endotoxic shock. Resistin binds to the LPS receptor, Toll-like receptor 4, through its N-terminal helix and triggers a switch from pro-inflammatory to anti-inflammatory responses. We hypothesize that resistin is a novel therapeutic for sepsis. We generated recombinant resistin and resistin N-terminal helices and tested their anti-inflammatory function in peripheral blood mononuclear cells (PBMC). Resistin, or its N-terminal helix alone, inhibited LPS-induced TNFa secretion by PBMC from healthy donors, but this inhibitory activity was abrogated without the helical structure. Next, we recruited 46 septic patients; 52% infection with LPS-rich gram-negative bacteria, and 30% mortality. Preliminary analysis revealed that circulating resistin was significantly higher in all septic patients compared to healthy donors, but that there were three distinct groups in the septic samples: high, medium and low resistin expression. Flow cytometry analysis revealed striking changes in immune cell subsets including monocytes, neutrophils, T cells and natural killer cells. Ongoing studies are investigating the immunomodulatory potential of resistin and its N-terminal helix in septic samples and associations with the infectious pathogen, circulating cytokines and immune cell subsets.