Formyl peptide receptor 2 orchestrates mucosal protection againstCitrobacter rodentiuminfection

Abstract

Citrobacter rodentium is an attaching and effacing intestinal murine pathogen which shares similar virulence strategies with the human pathogens enteropathogenic-and enterohemorrhagic Escherichia coli to infect their host. C. rodentium is spontaneously cleared by healthy wild-type (WT) mice whereas mice lacking Muc2 or specific immune regulatory genes demonstrate an impaired ability to combat the pathogen. Here we demonstrate that apical formyl peptide receptor 2 (Fpr2) expression increases in colonic epithelial cells during C. rodentium infection. Using a conventional inoculum dose of C. rodentium, both WT and Fpr2 −/− mice were infected and displayed similar signs of disease, although Fpr2 −/− mice recovered more slowly than WT mice. However, Fpr2 −/− mice exhibited increased susceptibility to C. rodentium colonization in response to low dose infection: 100% of the Fpr2 −/− and 30% of the WT mice became colonized and Fpr2 −/− mice developed more severe colitis and more C. rodentium were in contact with the colonic epithelial cells. In line with the larger amount of C. rodentium detected in the spleen in Fpr2 −/− mice, more C. rodentium and enteropathogenic Escherichia coli translocated across an in vitro mucosal surface to the basolateral compartment following FPR2 inhibitor treatment. Fpr2 −/− mice also lacked the striated inner mucus layer that was present in WT mice. Fpr2 −/− mice had decreased mucus production and different mucin O-glycosylation in the colon compared to WT mice, which may contribute to their defect inner mucus layer. Thus, Fpr2 contributes to protection against infection and influence mucus production, secretion and organization.

Gill Mucus and Gill Mucin O-glycosylation in Healthy and Amebic Gill Disease-Affected Atlantic Salmon

“…In the present study, we identified that the proportion of large glycans was higher among mucin glycans from infected gills than from uninfected gills. In the murine intestine, increased glycan size has been shown to be associated with decreased mucin biosynthesis rate due to longer time spent in the intracellular biosynthesis machinery [ 39 ]. Considering that mucus formation depends on multiple aspects, including mucin apoprotein production, glycosylation, secretion and ion composition [ 25 , 40 , 41 ], an alternative interpretation is therefore that these changes are caused by physiological changes and a decreased mucus turnover.…”

Cathelicidin-mediated lipopolysaccharide signaling via intracellular TLR4 in colonic epithelial cells evokes CXCL8 production

“…Based on in vitro studies, cathelicidins may influence migration of neutrophils to inflamed colons by chemoattraction, either directly via activation of FPR2 or indirectly by inducing pro-inflammatory cytokines (e.g., IL-1β, TNF-α, CXCL1). 17,19,34 Whereas fpr2 −/-and wildtype mice have similar colonic neutrophil recruitment during C. rodentium infection, 35 excluding an impact of cathelicidins on FPR2 activation, the role of cathelicidins in inducing the production of chemoattractants has been less explored. In our studies, we observed increased CXCL1 secretion in colons of Camp +/+ mice compared to Camp −/mice at the peak of C. rodentium infection (7 d pi) ( Figure 2a).…”

The Contribution of Chemoattractant GPCRs, Formylpeptide Receptors, to Inflammation and Cancer

“…In addition, mouse neutrophils expresses reduced levels of FPR2 (Fpr2) in a sepsis model (19,41), thus failing to infiltrate the site of infection. It is interesting that neutrophils in such sepsis subjects may be in an "inflamed" but "incompetent" state causing higher morbidity and mortality of the host (42).…”