The macrophage/tuft cell SUCNR1 axis in neonatal intestinal inflammation

University Of Oklahoma Hlth Sciences Ctr, Oklahoma City OK

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Abstract

RESEARCH PROJECT SUMMARY RPL: Kathryn Burge, PhD Project Title: The macrophage/tuft cell SUCNR1 axis in neonatal intestinal inflammation Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease of the neonatal period with an unclear, and likely multifactorial, pathogenesis. NEC most often affects preterm, very low birthweight (VLBW, < 1500 g) infants, and risk factors including dysbiosis, formula feeding, and prematurity have been implicated in NEC etiology. Our long-term goal is to identify interventions promoting healthy development of the intestine and gut microbiome during early life. Proinflammatory M1 macrophages infiltrate the preterm intestine during NEC, accelerating mucosal inflammation. In contrast, intestinal tuft cells, inducers of an anti-inflammatory, type 2 immune response, are depleted during murine ileitis. However, experimental expansion of tuft cells protects against ileal inflammation. Succinate accumulates in the NEC intestine, binding succinate receptor 1 (SUCNR1) in both mucosal macrophages and tuft cells. While the former perpetuates mucosal inflammation, the latter induces a tuft cell-mediated anti-inflammatory response, establishing a potential macrophage/tuft cell SUCNR1 axis in the regulation of mucosal innate immunity. Increased passive diffusion and transepithelial transport of succinate across a porous preterm intestinal barrier, enhanced hypoxia-induced succinate production within mucosal macrophages, and inflammation-induced tuft cell loss likely contribute to mucosal accumulation of succinate and ‘runaway inflammation’ typical of NEC. Our central hypothesis is that the macrophage/tuft cell SUCNR1 axis is dysregulated during NEC. Our preliminary data suggest tuft cells are depleted during preterm NEC pathogenesis. This project will test the hypotheses that (Aim 1) inhibition of macrophage SUCNR1 signaling and expansion of tuft cells and tuft cell-associated SUCNR1 signaling, in mice and preterm enteroid coculture models, will protect against NEC-like injury and that (Aim 2) preterm NEC will be associated with increased mucosal M1 macrophage SUCNR1 expression, increased expression of transporters directing epithelial succinate uptake, and decreased tuft cell numbers and SUCNR1 expression compared with age-matched controls. The overarching goal of this project is to provide novel cell-type-specific molecular targets for NEC, a disease subject to little clinical improvement within the past few decades. Successful completion of this project will enhance our mechanistic understanding of NEC, offering potential treatment targets for improved patient outcomes in a disease with no effective therapeutics beyond surgical intervention and supportive care, and no effective prophylactic alternatives to human milk.