Secreted Akkermansia muciniphila threonyl-tRNA synthetase functions to monitor and modulate immune homeostasis

Commensal bacteria are critically involved in the establishment of tolerance against inflammatory challenges, the molecular mechanisms of which are just being uncovered. All kingdoms of life produce aminoacyl-tRNA synthetases (ARSs). Thus far, the non-translational roles of ARSs have largely been reported in eukaryotes. Here, we report that the threonyl-tRNA synthetase (AmTARS) of the gut-associated bacterium Akkermansia muciniphila is secreted and functions to monitor and modulate immune homeostasis. Secreted AmTARS triggers M2 macrophage polarization and orchestrates the production of anti-inflammatory IL-10 via its unique, evolutionary-acquired regions, which mediates specific interactions with TLR2. This interaction activates the MAPK and PI3K/AKT signaling pathways, which converge on CREB, leading to an efficient production of IL-10 and suppression of the central inflammatory mediator NF-κB. AmTARS restores IL-10-positive macrophages, increases IL-10 levels in the serum, and attenuates the pathological effects in colitis mice. Thus, commensal tRNA synthetases can act as intrinsic mediators that maintain homeostasis. [Display omitted] •Gut-associated Akkermansia muciniphila secretes threonyl-tRNA synthetase (AmTARS)•Secreted AmTARS targets macrophages and activates the anti-inflammatory TLR2-CREB axis•An evolutionarily acquired region in AmTARS mediates specific interactions with TLR2•AmTARS restores macrophage homeostasis, increases IL-10, and attenuates colitis in mice Kim et al. report that the gut-associated bacterium A. muciniphila secretes threonyl-tRNA synthetase (AmTARS) to monitor and modulate host immune homeostasis. Secreted AmTARS activates anti-inflammatory signaling, restores macrophage homeostasis, increases IL-10, and attenuates colitis in mice. Commensal tRNA synthetases may act as intrinsic mediators that maintain homeostasis.