Axl alleviates DSS-induced colitis by preventing dysbiosis of gut microbiota.

Axl is a tyrosine kinase receptor, a negative regulator for innate immune responses and inflammatory bowel disease (IBD). The gut microbiota regulates intestinal immune homeostasis, but the role of Axl in the pathogenesis of IBD through the regulation of gut microbiota composition remains unresolved. In this study, mice with DSS-induced colitis showed increased Axl expression, which was almost entirely suppressed by depleting the gut microbiota with antibiotics. Axl-/- mice without DSS administration exhibited increased bacterial loads, especially the Proteobacteria abundant in patients with IBD, significantly consistent with DSS-induced colitis mice. Axl-/- mice also had an inflammatory intestinal microenvironment with reduced antimicrobial peptides and overexpression of inflammatory cytokines. The onset of DSS-induced colitis occurred faster with an abnormal expansion of Proteobacteria in Axl-/- mice than in WT mice. These findings suggest that a lack of Axl signaling exacerbates colitis by inducing aberrant compositions of the gut microbiota in conjunction with an inflammatory gut microenvironment. In conclusion, the data demonstrated that Axl signaling could ameliorate the pathogenesis of colitis by preventing dysbiosis of gut microbiota. Therefore, Axl may act as a potential novel biomarker for IBD and can be a potential candidate for the prophylactic or therapeutic target of diverse microbiota dysbiosis-related diseases.

Cyclophilin A is an endogenous ligand for the triggering receptor expressed on myeloid cells-2 (TREM2).

Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface receptor expressed on macrophages, microglial cells, and pre-osteoclasts, and that participates in diverse cellular function, including inflammation, bone homeostasis, neurological development, and coagulation. In spite of the indispensable role of the TREM2 protein in the maintenance of immune homeostasis and osteoclast differentiation, the exact ligand for TREM2 has not yet been identified. Here, we report a putative TREM2 ligand which is secreted from MC38 cells and identified as a cyclophilin A (CypA). A specific interaction between CypA and TREM2 was shown at both protein and cellular levels. Exogenous CypA specifically interacted and co-localized with TREM2 in RAW264.7 cells, and the physical interactions were shown to regulate TREM2 signaling transduction. The Pro144 residue in the extracellular domain of TREM2 was found to be the specific binding site of CypA. When considered together, this provides evidence that CypA interacts specifically with TREM2 as a potent ligand.