Intestinal macrophages: unique effector cells of the innate immune system

Abstract

The gastrointestinal mucosa is the largest reservoir of macrophages in the body. These important effector cells are derived from blood monocytes that are recruited to the lamina propria by endogenous chemoattractants in the non-inflamed mucosa and by inflammatory chemokines and bacterial products during inflammation. In the non-inflamed mucosa, newly recruited pro-inflammatory monocytes are exposed to lamina propria stromal (extracellular matrix) factors that induce phenotypic and functional differentiation into non-inflammatory macrophages. As a consequence of this differentiation, resident lamina propria macrophages are strikingly downregulated for the expression of innate response receptors, such as the receptors for lipopolysaccharide, immunoglobulin G (IgG), and IgA, and the production of pro-inflammatory cytokines, including interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor-alpha. Despite downregulated pro-inflammatory function, strong phagocytic and bactericidal activities remain intact. Thus, in the non-inflamed intestinal mucosa, lamina propria macrophages are non-inflammatory but retain avid scavenger and host defense functions, a unique but ideal phenotype and functional profile for effector cells in close proximity to immunostimulatory microorganisms and products.

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

“…In UC as well as in CD, excessive activation of the innate immunity initiates the inflammatory process, which is a prerequisite of the activation of the adaptive immune system, the latter being the main cause of tissue damage in IBD. 2,5 A similar mechanism is postulated in PSC except that Kupffer cells are not directly exposed to luminal gut microbes but to bacterial and pathogenic material from the portal vein. rs3197999 is one of the few SNPs associated with three different disease entities, UC, CD and PSC, which although distinct from each other share a common macrophage-dependent initiation mechanism.…”

“…In UC as well as in CD, excessive activation of innate immunity seems to initiate inflammation and to be a prerequisite for the activation of the adaptive immune system. 2,5 In 2.4% of all patients, IBD is accompanied by primary sclerosing cholangitis (PSC), a chronic inflammatory and cholestatic liver disease, 6 which is, inter alia, characterized by the accumulation of macrophages in sinusoidal and perisinusoidal spaces. 7 In all, 75 --90% of PSC patients have a history of or a co-existing IBD.…”

TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration

“…The degree of elevation of CXCL8 abundance is correlated with both disease activity and sigmoidoscopic severity in the dialysate bags 39 and with increased levels of infiltration of neutrophils in ulcerative colitis mucosa 40 . Notably, chronic inflammatory bowel diseases are mediated by activated monocytes and macrophages 41,42 , whereas induction of CXCL8 expression is induced in the lamina propria macrophages of ulcerative colitis mucosa 43 . Kupffer cells, the resident liver macrophages, produce and release various proinflammatory cytokines, including CXCL8, leading to exacerbation of inflammatory liver disease 44 , and CXCL8 produced by alveolar macrophages is involved in the development of chronic obstructive pulmonary disease 45 .…”

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

“…This dampening effect of the MSP/MST1R pathway on macrophages activation in response to microbial ligands, may be of particular interest in the intestinal epithelium where the innate immune system is under constant challenge, due to close contact with a variety of microorganisms. The loss of macrophage hyporesponsiveness or anergy has been proposed as a potential mechanism for triggering local inflammation and ultimately aspects of adaptive immunity implicated in IBD (51)(52)(53). The capacity of MSP to control IL-12p40 gene expression, a subunit of the heterodimeric IL-23, is also interesting in the context of IBD given the recent observations showing that IL23 regulation plays a central role in the control of intestinal inflammation (54,55) and that neutralizing anti-IL-12p40 antibodies prevent the development of disease in murine models of IBD (56,57).…”