Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection

Commensal flora can promote both immunity to pathogens and mucosal inflammation. How commensal driven inflammation is regulated in the context of infection remains poorly understood. Here, we show that during acute mucosal infection, Ly6C(hi) inflammatory monocytes acquire a tissue specific regulatory phenotype associated with production of the lipid mediator prostaglandin E(2) (PGE(2)). Notably, in response to commensals, Ly6C(hi) monocytes can directly inhibit neutrophil activation in a PGE(2)-dependent manner. Further, in the absence of inflammatory monocytes, mice develop severe neutrophil-mediated pathology that can be controlled by PGE(2) analog treatment. Complementing these findings, inhibition of PGE(2) led to enhanced neutrophil activation and host mortality. These data demonstrate a previously unappreciated dual action of inflammatory monocytes in controlling pathogen expansion while limiting commensal mediated damage to the gut. Collectively, our results place inflammatory monocyte derived PGE(2) at the center of a commensal driven regulatory loop required to control host-commensal dialogue during inflammation.