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Neuromedin U Attenuates Inflammation in a Murine Model of Hirschsprung-Associated Enterocolitis
Leah C. Ott1 Takahiro Ohkura1, Rhian Stavely1, Christopher Y. Han1, Ryo Hotta1, Allan M. Goldstein1 1Massachusetts General Hospital, Boston, MA

Background: Hirschsprung-associated enterocolitis (HAEC) is the most serious complication of Hirschsprung disease (HSCR). Impaired mucosal immunity is likely a contributing factor. Group 2 innate lymphoid cells (ILC2s) regulate mucosal immunity and are stimulated by the neurotransmitter neuromedin U (NMU) from enteric neurons. It is unknown whether activated colonic ILC2s can attenuate HAEC.

Methods: ILC2s (CD3-KLRG1+ cells), leukocytes (CD45+ cells), and neutrophils (S100a+ cells) were quantified in the colon of P21 wild-type (WT) and Ednrb knockout (Ednrb-/-) mice (n = 2) per high power field by fluorescent immunohistochemistry. Leukocyte and neutrophil infiltration were surrogate measures of colitis. P20 Ednrb-/- mice received recombinant NMU (1 g/g) or saline vehicle once i.p. (n = 2), then were sacrificed 72 hours post-injection. Colonic ILC2s, leukocytes, and neutrophils were quantified, and results analyzed using the two-tailed t test.

Results: P21 Ednrb-/- mice demonstrated prominent leukocyte and neutrophil infiltration in the distal colon consistent with colitis (Fig. 1A, p=0.003; Fig. 1B, p<0.0001) and had significantly fewer ILC2s than WT mice (Fig. 1C, p=0.001). While NMU injection did not stimulate significant ILC2 expansion in the distal colon compared to vehicle (Fig. 1F, p=0.265), it significantly reduced leukocyte and neutrophil infiltration, consistent with markedly decreased inflammation (Fig. 1D, p=0.004; Fig. 1E, p<0.0001).

Conclusion: Ednrb-/- mice have fewer colonic ILC2s compared to WT mice, likely due to absent enteric neuronal signaling. NMU decreases colonic inflammation in these mice, suggesting that restoration of neuroimmune signaling through ILC2s may be a promising treatment for HAEC.
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