Review ArticleToll-like receptor-mediated immune responses in intestinal macrophages; implications for mucosal immunity and autoimmune diseases
Introduction
The human intestinal tract harbors 1012 microorganisms per gram of luminal content, representing ten times more than that of human cells in the body [1], [2]. It is exposed constantly to massive foreign antigens and must discriminate between harmful and harmless antigens to ensure the normal function and homeostasis [3], [4]. The intestinal cells rapidly respond to different stimuli including microorganisms [4], [5], [6]. Meanwhile, the mucous barrier provides perfect protection against the diversity of bacteria residing in the lumen [7], [8]. Therefore, the interaction and conjunction between intestinal cells and luminal bacteria in the gut are identified to be crucial in maintaining intestinal homeostasis and are believed as “firewalls” for protection from the pathogens [1]. In the gut, mononuclear phagocyte system (MPS) maintains a delicate equilibrium between the induction of immune responses to potential pathogens and the tolerance to innocuous antigens [9]. Macrophages are major mononuclear phagocytes that play a crucial role in intestinal homeostasis and immunity [10], [11]. Monocytes in both human and mice are key players during inflammation and pathogen challenge in the periphery, whereas intestinal resident macrophages act as innate effector cells to engulf and clear bacteria or their products, secrete cytokines, and maintain intestinal homeostasis [10], [11]. However, perturbations between immunity and tolerance in the intestinal system have been shown to be associated with autoimmune diseases [12], including inflammatory bowel disease (IBD) [13], [14], systemic lupus erythematous (SLE) [15], [16], [17], type 1 diabetes (T1D) [18], [19], rheumatoid arthritis (RA) [20], and multiple sclerosis (MS) [21]. In this review, we have discussed the phenotypic characterization and function of intestinal macrophages, their subpopulations, and involvement in autoimmune diseases.
Section snippets
The origin and function of monocytes and macrophages in the intestine
Monocytes are a conserved population of leukocytes and play a central role in immune system [22], [23]. The homeostasis of tissue resident macrophages relies on the constant recruitment of blood monocytes [10], [11]. Recent studies showed that resident macrophages in mice are part of the MPS that arise from the hematopoietic system, which are constituted by self-renewal hematopoietic stem cells and progenitor cells in primary lymphoid organs [10], [11]. In human, monocytes express multiple
TLRs expression and stimulation on macrophages in gut
TLRs are key initiators of innate immune responses and promote adaptive immunity [49]. The most important cell types expressing TLRs are APCs, including macrophages, DCs, and B lymphocytes, which directly recognize various microbial pathogens through PAMPs [49], [50]. TLR engagement triggers downstream signaling pathways and ultimately results in antimicrobial responses [49], [51]. Intestinal macrophages, which represent a unique population of cells that exist in the gut, express most TLRs in
IBD
There is increasing evidence that mice knock out individual TLRs or MyD88 can trigger an abnormal inflammatory response of resident intestinal macrophages and thereby facilitate the development of IBD [58], [59], [60], [61]. As we know, to keep human intestinal homeostasis, intestinal macrophages have reduced CD14 expression and do not produce inflammatory cytokines through TLRs, although they remain phagocytic and bactericidal activities in the healthy human gut [44], [58], [62]. Moreover,
Conclusion
To inform future research, refining the phenotypic characterization of human intestinal monocyte/macrophage subpopulations would facilitate further investigation of their involvement in autoimmune diseases. Further investigation into the direct interactions between gut microbiota and intestinal macrophages in autoimmune diseases may elucidate how macrophage responses are generated and regulated by the dynamic adjustment of microorganisms. In conclusion, an increased understanding on these
Acknowledgements
The funding support was from the National Institute of Allergy and Infectious Diseases grant AI091526 and AI077283, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant P60 AR062755, UL1 RR029882, the Medical Research Service at the Ralph H. Johnson VA Medical Center Merit grant VA CSRD MERIT (CX001211), BLRD MERIT (BX000470), the 12th Five Year Research Project of People's Liberation Army (CWS11J160), Beijing Natural Science Foundation (Grant No. 7152063) and Scientific
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