Long noncoding RNAs (lncRNAs) have been implicated in the development of ulcerative colitis through the regulation of miRNA expression or modulation of intestinal epithelial barrier function. In Cell Metabolism, Shmuel-Galia et al. show that the lncRNA HOXA11os regulates myeloid cell metabolism in the colon to maintain intestinal homeostasis, and this may have a role in ulcerative colitis. Transcriptomic analysis was performed on myeloid cells from control mice and mice treated with dextran sulfate sodium to induce colitis; HOXA11os was expressed in the healthy distal colon and downregulated during inflammation. A similar pattern was detected in human tissue and HOXA11os expression was reduced in individuals with ulcerative colitis in a manner that correlated with disease severity. HOXA11os localized to the mitochondria and HOXS11os-deficient mice had impaired OXPHOS, developed age-dependent spontaneous intestinal inflammation, and were more susceptible to experimental models of colitis. HOXA11os-deficient myeloid cells had impaired complex I activity and dysfunctional mitochondria. When mitochondrial reactive oxygen species were depleted in HOXA11os-deficient mice, colitis was ameliorated. Together, the findings suggest that HOXA11os maintains intestinal homeostasis and restricts inflammation by regulation of complex I activity in myeloid cells.
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