Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection

Abstract

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, Ly6Chi inflammatory monocytes acquire a tissue specific regulatory phenotype associated with production of the lipid mediator prostaglandin E2 (PGE2). Notably, in response to commensals, Ly6Chi monocytes can directly inhibit neutrophil activation in a PGE2-dependent manner. Further, in the absence of inflammatory monocytes, mice develop severe neutrophil-mediated pathology that can be controlled by PGE2 analog treatment. Complementing these findings, inhibition of PGE2 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 PGE2 at the center of a commensal driven regulatory loop required to control host-commensal dialogue during inflammation.

Gastroenterology issues in schizophrenia: Why the gut matters

“…Interestingly, T. gondii exposure is a well-documented risk factor for schizophrenia [83,84], and as a gut pathogen is a tool used in experimental models to produce an inflammatory state in the GI tract. Thus not surprisingly, T. gondii infection can drive the dysbiosis of resident microbial communities and bring about a state of increased GI permeability [85][86][87][88]. In our studies of clinical samples, we found correlations between levels of T. gondii IgG with food antigen IgG in people with a recent onset of schizophrenia, which were not present in control groups [13].…”

Ly6Chigh Monocytes Protect against Kidney Damage during Sepsis via a CX3CR1-Dependent Adhesion Mechanism

“…5,[35][36][37] Recent studies have identified a regulatory protective role for inflammatory monocytes in infectious diseases as they synthetize and secrete anti-inflammatory mediators, such as IL-1ra and prostaglandin E2. 8,9 However, the specific contribution of inflammatory monocytes to the regulation of inflammation in early phases of sepsis remains unclear. Our results have unveiled a key role these monocytes play in renal tissue protection via a CX3CR1-dependent adhesion of inflammatory monocytes to the renal vascular endothelium.…”

“…Previous studies have shown that inflammatory monocytes are involved in controlling inflammation in gram-negative pneumonia and abdominal infections. 8,9,[38][39][40][41][42] A lower number of inflammatory monocytes has been associated with increased lesions in the lung and in the intestinal lamina propria. 8,9,38,41 Other studies have shown that the CX3CR1/ CX3CL1 axis is involved in the pathogenesis of sepsis.…”

“…They protect tissues during infectious processes, such as pneumonia or gastrointestinal toxoplasmosis, notably via their secretion of IL-1 receptor antagonist 9,12,13 (IL-1ra) or prostaglandin E2. 8 Essential crosstalk among monocytes, neutrophils, and tissue (especially epithelial cells) controls the equilibrium between inflammatory and anti-inflammatory processes.…”

Diversity and functions of intestinal mononuclear phagocytes

“…198,199 Inflammatory monocytes themselves have been shown to inhibit the pathological effects of neutrophils during the intestinal inflammation induced by DSS or Toxoplasma gondii. 154,174 In the latter case, this reflected synthesis of PGE2…”