Abstract
Macrophages (Mϕs) are known to be major producers of the anti-inflammatory cytokine interleukin-10 (IL-10) in the intestine, thus playing an important role in maintaining gastrointestinal homeostasis. Mϕs that reside in the small intestine (SI) have been previously shown to be regulated by dietary antigens, while colonic Mϕs are regulated by the microbiota. However, the role which resident Mϕs play in SI homeostasis has not yet been fully elucidated. Here, we show that SI Mϕs regulate the integrity of the epithelial barrier via secretion of IL-10. We used an animal model of non-steroidal anti-inflammatory drug (NSAID)-induced SI epithelial injury to show that IL-10 is mainly produced by MHCII+ CD64+ Ly6Clow Mϕs early in injury and that it is involved in the restoration of the epithelial barrier. We found that a lack of IL-10, particularly its secretion by Mϕs, compromised the recovery of SI epithelial barrier. IL-10 production by MHCII+ CD64+ Ly6Clow Mϕs in the SI is not regulated by the gut microbiota, hence depletion of the microbiota did not influence epithelial regeneration in the SI. Collectively, these results highlight the critical role IL-10-producing Mϕs play in recovery from intestinal epithelial injury induced by NSAID.
Highlights
The intestine contains the largest pool of macrophages (Mφs) in the body
Consistent with this, we have previously reported that IL-10-producing Mφs in the small intestine (SI) are regulated by dietary factors[16]
Body weight loss corresponded with increased intestinal permeability, as quantified by a fluorescein isothiocyanate (FITC) dextran assay as well as endoscopic findings of ulceration and hemorrhage (Fig. 1b,c)
Summary
The intestine contains the largest pool of macrophages (Mφs) in the body. They produce the anti-inflammatory cytokine interleukin (IL)-10, which is essential for the maintenance of mucosal homeostasis[1,2,3]. The IL-10-producing Mφs in the SI are less abundant and produce less IL-10 in a total parenteral nutrition mouse model in which mice do not experience enteral stimulation by dietary antigens[16] This animal model is associated with gut translocation and impairments of the intestinal barrier[16]. In order to study the role Mφs play in maintaining homeostasis in the SI, we employed the non-steroidal anti-inflammatory drug (NSAID)-induced epithelial injury model. The mechanism and appropriate treatment of NSAID-induced SI injury have not been completely elucidated Using this mouse model, we determined that IL-10-producing MHCII+ CD64+ Ly6Clow Mφs play an essential role in the recovery from acute SI injury
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