Role of Macrophages and Mast Cells as Key Players in the Maintenance of Gastrointestinal Smooth Muscle Homeostasis and Disease
2022; Elsevier BV; Volume: 13; Issue: 6 Linguagem: Inglês
10.1016/j.jcmgh.2022.02.017
ISSN2352-345X
AutoresMagdalini Mischopoulou, Mario D’Ambrosio, Elisabetta Bigagli, Cristina Luceri, Gianrico Farrugia, Gianluca Cipriani,
Tópico(s)Gut microbiota and health
ResumoThe gut contains the largest macrophage pool in the body, with populations of macrophages residing in the mucosa and muscularis propria of the gastrointestinal (GI) tract. Muscularis macrophages (MMs), which are located within the muscularis propria, interact with cells essential for GI function, such as interstitial cells of Cajal, enteric neurons, smooth muscle cells, enteric glia, and fibroblast-like cells, suggesting that these immune cells contribute to several aspects of GI function. This review focuses on the latest insights on the factors contributing to MM heterogeneity and the functional interaction of MMs with other cell types essential for GI function. This review integrates the latest findings on macrophages in other organs with increasing knowledge of MMs to better understand their role in a healthy and diseased gut. We describe the factors that contribute to (muscularis macrophage) MM heterogeneity, and the nature of MM interactions with cells regulating GI function. Finally, we also describe the increasing evidence suggesting a critical role of another immune cell type, the mast cell, in normal and diseased GI physiology. The gut contains the largest macrophage pool in the body, with populations of macrophages residing in the mucosa and muscularis propria of the gastrointestinal (GI) tract. Muscularis macrophages (MMs), which are located within the muscularis propria, interact with cells essential for GI function, such as interstitial cells of Cajal, enteric neurons, smooth muscle cells, enteric glia, and fibroblast-like cells, suggesting that these immune cells contribute to several aspects of GI function. This review focuses on the latest insights on the factors contributing to MM heterogeneity and the functional interaction of MMs with other cell types essential for GI function. This review integrates the latest findings on macrophages in other organs with increasing knowledge of MMs to better understand their role in a healthy and diseased gut. We describe the factors that contribute to (muscularis macrophage) MM heterogeneity, and the nature of MM interactions with cells regulating GI function. Finally, we also describe the increasing evidence suggesting a critical role of another immune cell type, the mast cell, in normal and diseased GI physiology. SummaryThis review describes the factors contributing to muscularis macrophage heterogeneity and the nature of muscularis macrophage's interactions with cells that regulate gastrointestinal function. The emerging role of mast cells in gastrointestinal homeostasis and diseases also is described. This review describes the factors contributing to muscularis macrophage heterogeneity and the nature of muscularis macrophage's interactions with cells that regulate gastrointestinal function. The emerging role of mast cells in gastrointestinal homeostasis and diseases also is described. Early studies based on electron microscopy and immunohistochemistry identified "macrophage-like cells" in the muscularis propria of the gut.1Rumessen J.J. Thuneberg L. Mikkelsen H.B. Plexus muscularis profundus and associated interstitial cells. II. Ultrastructural studies of mouse small intestine.Anat. Rec. 1982; 203: 129-146Crossref Scopus (94) Google Scholar, 2Mikkelsen H.B. Thuneberg L. Rumessen J.J. Thorball N. Macrophage-like cells in the muscularis externa of mouse small intestine.Anat. Rec. 1985; 213: 77-86Crossref PubMed Google Scholar, 3Mikkelsen H.B. Macrophages in the external muscle layers of mammalian intestines.Histol. Histopathol. 1995; 10: 719-736PubMed Google Scholar, 4Mikkelsen H.B. Thuneberg L. Wittrup I.H. 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Diabetic Csf1op/op mice lacking macrophages are protected against the development of delayed gastric emptying.Cell. Mol. Gastroenterol. Hepatol. 2016; 2: 40-47Abstract Full Text Full Text PDF PubMed Google Scholar MMs share a general anti-inflammatory phenotype at steady-state conditions compared with mucosal macrophages, which, in contrast, have an overall inflammatory phenotype.15Gabanyi I. Muller P.A. Feighery L. Oliveira T.Y. Costa-Pinto F.A. Mucida D. Neuro-immune interactions drive tissue programming in intestinal macrophages.Cell. 2016; 164: 378-391Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar,16Mowat A.M. Bain C.C. Mucosal macrophages in intestinal homeostasis and inflammation.J. Innate Immun. 2011; 3: 550-564Crossref Scopus (159) Google Scholar This may be a consequence of the location of MMs because the mucosa is constantly exposed to external stimuli. In addition, MMs share wound healing and tissue-protective genes such as Rental (encoding Fizz1), Mrc1, Cd163, and Il10.17Wehner S. Engel D.R. Resident macrophages in the healthy and inflamed intestinal muscularis externa.Pflugers Arch. – Eur. J. Physiol. 2017; 469: 541-552Crossref Scopus (11) Google Scholar,18Bujko A. Atlasy N. Landsverk O.J.B. Richter L. Yaqub S. Horneland R. Øyen O. Aandahl E.M. Aabakken L. Stunnenberg H.G. Bækkevold E.S. Jahnsen F.L. Transcriptional and functional profiling defines human small intestinal macrophage subsets.J. Exp. Med. 2018; 215: 441-458Crossref PubMed Scopus (77) Google Scholar Contrary to the increasing understanding of the murine MM phenotype complexity, human MM information is limited and relies heavily on immunohistochemistry and morphology-based studies. Similar to the observations obtained in mice, transition of monocytes to a tissue-resident phenotype has been described in mucosal macrophages, where a population of monocytes sharing CD14high C-C Motif Chemokine Receptor 2 (CCR2+)CD11chigh markers is transitioning to a CD14lowCCR2-CD11chigh macrophage phenotype.19Bernardo D. Marin A.C. Fernández-Tomé S. et al.Human intestinal pro-inflammatory CD11c(high)CCR2(+)CX3CR1(+) macrophages, but not their tolerogenic CD11c(-)CCR2(-)CX3CR1(-) counterparts, are expanded in inflammatory bowel disease.Mucosal Immunol. 2018; 11: 1114-1126Crossref PubMed Scopus (56) Google Scholar Further investigations are needed to provide information about the composition and distribution of human MMs to understand the degree of similarities with murine MMs. Overall, the heterogeneity of the MM phenotype (Figure 1) depends mostly on the origin and location in different regions of the gut (interdiversity) and between different regions across the muscularis propria (intradiversity). For a long time, it has been thought that resident macrophages were continuously replenished by circulating monocytes.20van Furth R. Cohn Z.A. The origin and kinetics of mononuclear phagocytes.J. Exp. 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Baekelandt V. Gonzalez Dominguez E. Mack M. Depoortere I. De Strooper B. Sprangers B. Himmelreich U. Soenen S. Guilliams M. Vanden Berghe P. Jones E. Lambrechts D. Boeckxstaens G. Self-maintaining gut macrophages are essential for intestinal homeostasis.Cell. 2019; 176: 676Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar identified a population of MMs in the small intestine that engrafted the GI tract during the embryonic state. This population of embryonic origin is known as long-lived MMs because it persists in the muscularis propria depending exclusively on cell proliferation. Besides this population, throughout life, the muscularis propria is populated primarily by monocyte-derived MMs that continuously replenish tissue-resident MMs. Monocyte- and embryonic-derived MMs represent the entire pool of tissue-resident MMs. In the same study, the investigators provided evidence that this population of embryonic origin clusters near enteric neurons (ENs) and regulates their number. Pieces of evidence suggest the possible contribution of monocyte-derived MMs to GI dysfunction. CCR2-dependent monocyte-derived macrophages play a role in resolving and restoring GI motility in postoperative ileus.24Farro G. Stakenborg M. Gomez-Pinilla P.J. Labeeuw E. Goverse G. Di Giovangiulio M. Stakenborg N. Meroni E. D'Errico F. Elkrim Y. Laoui D. Lisowski Z.M. Sauter K.A. Hume D.A. Van Ginderachter J.A. Boeckxstaens G.E. Matteoli G. CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus.Gut. 2017; 66: 2098-2109Crossref Scopus (45) Google Scholar In diabetic mice with gastroparesis, an increased number of MMs25Choi K.M. Kashyap P.C. Dutta N. Stoltz G.J. Ordog T. Shea Donohue T. Bauer A.J. Linden D.R. Szurszewski J.H. Gibbons S.J. Farrugia G. CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice.Gastroenterol. 2010; 138 (2409.e1): 2399-2409Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar coincides with a higher level of MMs expressing proinflammatory markers,26Cipriani G. Gibbons S.J. Miller K.E. Yang D.S. Terhaar M.L. Eisenman S.T. Ördög T. Linden D.R. Gajdos G.B. Szurszewski J.H. Farrugia G. Change in populations of macrophages promotes development of delayed gastric emptying in Mice.Gastroenterol. 2018; 154 (e12): 2122-2136Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar which can depend on increased recruitment of monocytes. A recent study27Moura Silva H. Kitoko J.Z. Queiroz C.P. Kroehling L. Matheis F. Yang K.L. Reis B.S. Ren-Fielding C. Littman D.R. Bozza M.T. Mucida D. Lafaille J.J. c-MAF-dependent perivascular macrophages regulate diet-induced metabolic syndrome.Sci Immunol. 2021 Oct; 6: eabg7506Crossref Scopus (1) Google Scholar identified a population of MMs closely associated with blood vessels in the GI muscularis called perivascular MMs. This population of MMs is regulated by the transcription factor Maf, which also controls the expression of several genes associated with the anti-inflammatory MMs. This population of MMs related to adipose tissue overlap with CD206 MMs. Interestingly, using a lineage tracing mouse model, the investigators clearly showed that this population is not dependent on circulating monocytes and primarly of embryonic origin. Conditional removal of the transcription factor c-MAF from MMs leads to CD206 macrophage loss. Immune cell diversity has been described in 3 commonly used murine strains (C57BL/6NCr, 129/SvHsd, and BALB/cAnNCr).28Hensel J.A. Khattar V. Ashton R. Ponnazhagan S. 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Analysis of genetically diverse macrophages reveals local and domain-wide mechanisms that control transcription factor binding and function.Cell. 2018; 173 (e17): 1796-1809Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar driving macrophage phenotype. In addition, macrophages from BALB/cAnNCr and C57BL/6NCr respond differently to corneal transplantation.30Bleul T. Zhuang X. Hildebrand A. Lange C. Böhringer D. Schlunck G. Reinhard T. Lapp T. Different innate immune responses in BALB/c and C57BL/6 strains following corneal transplantation.J. Innate Immun. 2021; 13: 49-59Crossref Scopus (6) Google Scholar Almost all the information relative to MMs has been produced using C57BL/6NCr mice except for some studies on nonobese diabetic/ShiLtJ. Notably, as an indication of variability in MM phenotype owing to mouse strain, at steady-state conditions, nonobese diabetic mice do not express25Choi K.M. Kashyap P.C. Dutta N. Stoltz G.J. Ordog T. Shea Donohue T. Bauer A.J. Linden D.R. Szurszewski J.H. Gibbons S.J. Farrugia G. CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice.Gastroenterol. 2010; 138 (2409.e1): 2399-2409Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar CD206, which otherwise is highly expressed in tissue-resident MMs in C57BL/6NCr mice. As microglia in the central nervous system (CNS), MM phenotype depends on regional distribution across the smooth muscle layers and their interaction with other cell types populating the same environment (intradiversity). MMs are diverse and dynamic,31Phillips R.J. Billingsley C.N. Powley T.L. Macrophages are unsuccessful in clearing aggregated alpha-synuclein from the gastrointestinal tract of healthy aged Fischer 344 rats.Anat Rec (Hoboken). 2013; 296: 654-669Crossref Scopus (15) Google Scholar,32Ji S. Traini C. Mischopoulou M. Gibbons S.J. Ligresti G. Faussone-Pellegrini M.S. Sha L. Farrugia G. Vannucchi M.G. Cipriani G. Muscularis macrophages establish cell-to-cell contacts with telocytes/PDGFRα-positive cells and smooth muscle cells in the human and mouse gastrointestinal tract.Neurogastroenterol. Motil. 2021; 33e13993Crossref Scopus (9) Google Scholar and show a different morphology depending on their location. MMs can be divided into 3 distinct populations based on their distribution within the smooth muscle layers. MMs located in the myenteric plexus and serosal regions are multipolar, with many branches originating from the main body. MMs located within the muscular layers have a bipolar morphology following the muscle cell orientation. Further data are needed to understand if the morphologic differences between these diverse MM populations translate into functional changes. A recent study23De Schepper S. Verheijden S. Aguilera-Lizarraga J. Viola M.F. Boesmans W. Stakenborg N. Voytyuk I. Schmidt I. Boeckx B. Dierckx de Casterlé I. Baekelandt V. Gonzalez Dominguez E. Mack M. Depoortere I. De Strooper B. Sprangers B. Himmelreich U. Soenen S. Guilliams M. Vanden Berghe P. Jones E. Lambrechts D. Boeckxstaens G. Self-maintaining gut macrophages are essential for intestinal homeostasis.Cell. 2019; 176: 676Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar associated a MM population with a specific area of the small intestine muscularis propria. De Schepper et al23De Schepper S. Verheijden S. Aguilera-Lizarraga J. Viola M.F. Boesmans W. Stakenborg N. Voytyuk I. Schmidt I. Boeckx B. Dierckx de Casterlé I. Baekelandt V. Gonzalez Dominguez E. Mack M. Depoortere I. De Strooper B. Sprangers B. Himmelreich U. Soenen S. Guilliams M. Vanden Berghe P. Jones E. Lambrechts D. Boeckxstaens G. Self-maintaining gut macrophages are essential for intestinal homeostasis.Cell. 2019; 176: 676Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar identified a MM population essential for EN maintenance, located within the myenteric plexus region where they interact with ENs. Although we have a clearer picture of MM distribution in different smooth muscle layers at steady-state conditions, we only have partial information about their distribution in states of altered homeostasis and disease. In aging,31Phillips R.J. Billingsley C.N. Powley T.L. Macrophages are unsuccessful in clearing aggregated alpha-synuclein from the gastrointestinal tract of healthy aged Fischer 344 rats.Anat Rec (Hoboken). 2013; 296: 654-669Crossref Scopus (15) Google Scholar clusters of CD163-IR immune cells were visualized in proximity to sympathetic hyperinnervation of the jejunum of rats. In a mouse model of diabetic gastroparesis, an increase in MM number was described25Choi K.M. Kashyap P.C. Dutta N. Stoltz G.J. Ordog T. Shea Donohue T. Bauer A.J. Linden D.R. Szurszewski J.H. Gibbons S.J. Farrugia G. CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice.Gastroenterol. 2010; 138 (2409.e1): 2399-2409Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar with the onset of diabetes, but no changes in the distribution of MMs has been reported. As briefly mentioned in the previous section, perivascular MMs27Moura Silva H. Kitoko J.Z. Queiroz C.P. Kroehling L. Matheis F. Yang K.L. Reis B.S. Ren-Fielding C. Littman D.R. Bozza M.T. Mucida D. Lafaille J.J. c-MAF-dependent perivascular macrophages regulate diet-induced metabolic syndrome.Sci Immunol. 2021 Oct; 6: eabg7506Crossref Scopus (1) Google Scholar, associated with an anti-inflammatory and protective phenotype, are localized within the myenteric plexus region, where the blood vessels are located in the GI muscularis propria. Another factor contributing to MM heterogeneity is the location of MMs within the different regions of the GI tract (interdiversity). We recently showed that MM distribution within the stomach and the small intestine presents some differences that require more attention in the future.32Ji S. Traini C. Mischopoulou M. Gibbons S.J. Ligresti G. Faussone-Pellegrini M.S. Sha L. Farrugia G. Vannucchi M.G. Cipriani G. Muscularis macrophages establish cell-to-cell contacts with telocytes/PDGFRα-positive cells and smooth muscle cells in the human and mouse gastrointestinal tract.Neurogastroenterol. Motil. 2021; 33e13993Crossref Scopus (9) Google Scholar MM distribution within the myenteric plexus and the smooth muscle layers were more homogenous in the stomach than in the small intestine. Gastric MMs are distributed evenly between the myenteric plexus and the smooth muscle layers, whereas small intestine MMs are distributed primarily in the myenteric plexus. Further studies are needed to understand if this critical difference in MM distribution also is responsible for functional changes. Phenotypically, at resting, gastric MMs do not express CD206 as MMs from the small intestine do. It also appeared that MMs in the different gut regions respond to external stimuli differently, suggesting a possible intrinsic phenotypic difference. For example, in diabetes, gastric MMs change their phenotype, leading to gastric dysfunction, whereas MMs in the small intestine appeared to be unchanged. More studies are needed to understand the differences between the populations of MMs residing in the different gut regions looking at the following: (1) phenotypic changes, (2) changes in response to inflammation/stimuli, and (3) origin. As previously described, one of the most critical factors contributing to MM heterogeneity is the tissue cue where MMs reside and interact with different cell types. 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