Microbial-dependent recruitment of immature myeloid cells promotes intestinal regeneration.

BACKGROUND & AIMS: The intestinal epithelium functions both in nutrient absorption and as a barrier, separating the luminal contents from a network of vascular, fibroblastic, and immune cells underneath. Following injury to the intestine, multiple cell populations cooperate to drive regeneration of the mucosal barrier, including lymphatic endothelial cells (LECs). A population of granulocytic immature myeloid cells (IMCs), marked by histidine decarboxylase (Hdc), participate in regeneration of multiple organs such as the colon and central nervous system, but their contribution to intestinal regeneration was unknown.

METHODS: Using male and female HdcGFP mice, we investigated the role of Hdc+ IMCs in intestinal regeneration after exposure to 12 Gy whole-body irradiation. The movement of IMCs was analyzed using flow cytometry and immunostaining. Ablation of Hdc+ cells using HdcCreERT2 ; R26DTA tamoxifen-inducible recombinase Cre system, conditional knockout of Ptgs2 in Hdc+ cells using HdcCre ; Ptgs2fl/fl mice, and visualization of LECs using Prox1tdTomato mice was also performed. The role of microbial signals was investigated by knocking down mice's gut microbiomes using antibiotic cocktail gavages.

RESULTS: We found that Hdc+ IMCs infiltrate the injured intestine following irradiation injury and promote epithelial regeneration in part by modulating LEC activity. Hdc+ IMCs express Ptgs2 (encoding COX-2), enables them to produce prostaglandin E2 (PGE2). PGE2 acts upon the EP4 receptor on LECs to promote lymphangiogenesis and induce the expression of pro-regenerative factors including RSPO3. Depletion of gut microbes leads to reduced intestinal regeneration by impaired recruitment of IMCs.

CONCLUSIONS: Altogether, our results unveil a critical role for IMCs in intestinal repair by modulating LEC activity and implicate gut microbes as mediators of intestinal regeneration.