Effects of acute ethanol exposure on post burn intestinal immunity: role of IL-23

Loyola University Chicago, Maywood IL

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Abstract

DESCRIPTION (provided by applicant): Alcohol is a contributing factor in post burn morbidity and mortality. Our laboratory has previously demonstrated that acute alcohol intoxication suppresses intestinal immune function and enhances bacterial translocation, yet the mechanism responsible for these observations remains unknown. Current evidence suggest that T helper (Th) 17 lymphocytes play a critical role in maintaining normal barrier function and minimizing invasion of bacteria across the intestinal epithelium. Additionally, interleukin IL-23, a cytokine released predominantly by dendritic cells, is crucial in Th17 differentiation and antimicrobial expression. Preliminary studies from our laboratory demonstrated decreased levels of Th17 effector cytokine IL-17 as well as decreased levels of the p40 subunit of IL-23 in Peyer's patches following alcohol intoxication and burn injury. Peyer's patches are small immune cell-containing lymphoid organs along the small intestine that are critical to bacterial containment. Based on these observations, we hypothesize that alcohol intoxication prior to burn injury disrupts IL-23 production from dendritic cells within Peyer'spatches, which in turn impairs Th17 effector functions and antimicrobial expression within the intestine. Three specific aims have been developed to examine this hypothesis. Aim 1 will establish the effects of acute alcohol exposure on post burn IL-23 release within the intestine and correlate these findings with altered secretion of Th17 cytokines IL-17 and IL-22 and antimicrobial expression. Aim 2 will determine if administration of recombinant IL- 23, improves intestinal Th17 effector functions and antimicrobial peptide expression following alcohol intoxication and burn injury. Aim 3 will focus on the role of STAT3 and ROR-3t activation in IL-23 mediated regulation of Th17 responses following alcohol intoxication and burn injury. Studies will be carried out using a mouse model of acute alcohol exposure and thermal injury. Overall, this proposal will yield novel data that may aid in the development of targeted therapeutic interventions for patients who sustain burn injury after exposure to alcohol.