Differential gene expression in the colons of mice lacking neuregulin-4

Growth factors are essential for maintenance of intestinal health at homeostasis and during inflammation. We have previously shown that exogenous treatment with the growth factor neuregulin-4 (NRG4) promotes colonocyte survival during cytokine challenge and is protective in acute models of intestinal inflammation. However, the role of endogenously expressed NRG4 in colitis is not well understood. Using NRG4-/- mice, we tested the effect of endogenous NRG4 on colitis. NRG4-/- and wild type cage-mate mice were subjected to an IL-10R neutralization model of chronic colitis. NRG4-/- mice displayed reduced inflammatory cytokine expression in the colon and a reduction in tissue CD8+ T cells at 5 weeks post induction of colitis. In unchallenged NRG4-/- mice, baseline numbers of colonic CD8+ T cell numbers were unchanged. However, there was a significant decrease in splenic CD8+ T cells. RNA sequencing from colonic homogenates showed a loss of St3gal4, a sialyltransferase involved in immune cell trafficking, in the NRG4-null animals. This loss was verified in both tissue and epithelium. The regulation of St3gal4 by NRG4 was confirmed with ex vivo epithelial colon organoid cultures from NRG4-/- mice and by induction of St3gal4 in vivo following NRG4 treatment. Together our data suggest that NRG4 regulates colonic epithelial ST3GAL4 and thus the recruitment of CD8+ T cells, but also has systemic effects on T cell maturation. These effects may combine to stimulate immune mediated inflammation during IL-10R neutralization colitis. Overall design: RNA-sequencing of full thickness colonic biopsies from 6 wildtype and 5 Nrg4-/- adult (11-12 wks-old) co-housed mice