Intestinal macrophages and response to microbial encroachment

Abstract

Macrophages in the gastrointestinal mucosa represent the largest pool of tissue macrophages in the body. In order to maintain mucosal homeostasis, resident intestinal macrophages uniquely do not express the lipopolysaccharide (LPS) co-receptor CD14 or the IgA (CD89) and IgG (CD16, 32, and 64) receptors, yet prominently display Toll-like receptors (TLRs) 3-9. Remarkably, intestinal macrophages also do not produce proinflammatory cytokines in response to TLR ligands, likely because of extracellular matrix (stroma) transforming growth factor-β dysregulations of nuclear factor (NF)-κB signal proteins and, via Smad signaling, expression of IκBα, thereby inhibiting NF-κB-mediated activities. Thus, in noninflamed mucosa, resident macrophages are inflammation anergic but retain avid scavenger and host defense function, an ideal profile for macrophages in close proximity to gut microbiota. In the event of impaired epithelial integrity during intestinal infection or inflammation, however, blood monoctyes also accumulate in the lamina propria and actively pursue invading microorganisms through uptake and degradation of the organism and release of inflammatory mediators. Consequently, resident intestinal macrophages are inflammation adverse, but when the need arises, they receive assistance from newly recruited circulating monocytes.

Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease

“…Whereas RON is not expressed in monocytes of the circulating blood, its expression could be demonstrated in macrophage precursor cells adhering to the vessel wall. 34,35,37 At this early stage of macrophage recruitment, the presence of MSP mut may impair the differentiation into resident intestinal macrophages but instead promote an inflammatory phenotype. This hypothesis is supported by the fact that MSP mut enhances a certain spectrum of macrophage functions, which is characteristic of the inflammatory phenotype of macrophages.…”

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

“…1 Intestinal macrophages have also been shown to have a central role in tolerance in the intestine. 2,3 Specific subsets of CD4 þ T helper (T H ) cells, primarily FOXP3-expressing regulatory T cells (T reg cells) and IL-17A-producing T H cells (T H 17 cells) are enriched in the intestinal lamina propria (LP), 4 whereas CD8 þ T cells and gd T cells are found in the intraepithelial compartment, 5 acting in conjunction with IgA-producing B cells that are required to maintain tolerance to the commensal flora. 6 However, the molecular mechanisms that regulate intestinal immune cell function in health and disease are not fully defined.…”

Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function

“…In health, these cells are characterized by a specific phenotype, CD33 + CD14 À , are highly anergic and do not produce pro-inflammatory cytokines in response to lipopolysaccaride (LPS) [8,9]. In IBD, however, intestinal macrophages express innate response receptors such as CD14 + , TREM-1, and release pro-inflammatory cytokines [10].…”