Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Sep 28:12:749708.
doi: 10.3389/fimmu.2021.749708. eCollection 2021.

Beyond Immunity: Underappreciated Functions of Intestinal Macrophages

Pailin Chiaranunt  1 , Siu Ling Tai  1 , Louis Ngai  1 , Arthur Mortha  1
Affiliations
Review

Beyond Immunity: Underappreciated Functions of Intestinal Macrophages

Pailin Chiaranunt et al. Front Immunol. .

Abstract

The gastrointestinal tract hosts the largest compartment of macrophages in the body, where they serve as mediators of host defense and immunity. Seeded in the complex tissue-environment of the gut, an array of both hematopoietic and non-hematopoietic cells forms their immediate neighborhood. Emerging data demonstrate that the functional diversity of intestinal macrophages reaches beyond classical immunity and includes underappreciated non-immune functions. In this review, we discuss recent advances in research on intestinal macrophage heterogeneity, with a particular focus on how non-immune functions of macrophages impact tissue homeostasis and function. We delve into the strategic localization of distinct gut macrophage populations, describe the potential factors that regulate their identity and functional heterogeneity within these locations, and provide open questions that we hope will inspire research dedicated to elucidating a holistic view on macrophage-tissue cell interactions in the body's largest mucosal organ.

Keywords: homeostasis; intestinal; macrophage; macrophages; monocytes; mucosal; niche.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Intestinal MP heterogeneity is determined by distinct ontogeny, transcription profiles, and microanatomic locations. (A) Fetal liver monocytes and adult BM-derived monocytes seed the intestinal tract in two distinct waves, giving rise to at least three distinct MP populations in the gut: Tim-4-CD4- (DN) MPs, Tim-4-CD4+ (SP) MPs, and Tim-4+CD4+ (DP) MPs. Monocytes require CCR2 and NR4A1 for the egress from the BM and differentiation into subsets. Monocytes have been suggested to differentiate into DN MPs in a RUNX3-dependent manner and in an environment rich in CSF1, whereas DP MPs require CSF1 and TGF-β. CSF2 plays a role in gut MP development and impacts the functional and developmental profile of MP, possibly through the actions of IRF5. However, the exact differentiation pathways and plasticity between DN, SP, and DP MPs are yet to be elucidated. The color separation (blue: fetal, light brown: adult) in (A) indicates the developmental origin of MPs. Dashed lines indicate potential developmental relationships among gut MPs. It remains unclear if DN, SP and DP MPs constituted a developmental continuum or follow three distinctly developmental pathways. Plasticity between each MP population also remains to be addressed. After birth, infiltration of adult BM-derived monocytes into the intestinal tract requires signals from the microbiome. (B) Post infiltration of the gut, MPs accumulate at distinct microanatomic locations across the intestinal tract. Close proximity with characteristic structures allows for the classification of intestinal MPs into vasculature-associated MPs (vMPs, red), epithelium-associated MPs (eMPs, light brown), nerve-associated MPs (nMPs, light blue) and lymphoid tissue-associated MPs (lMPs, violet). Despite their shared monocytic origin, there is evidence of preferential anatomic localization of MPs that has been factored into our current working model for intestinal MP development. (C) We propose a working model for gut MP development, in which precursors of distinct developmental origins (blue: fetal, light brown: adult) differentiate into DN, SP, and DP MPs. Colors indicate their accumulation at microanatomic locations like the vasculature (red), the epithelium (light brown), neurons (light blue) or lymphoid tissues (violet). Each MP identity depends on ontogeny, their microanatomic location, and the environmental signals therein. Dashed lines indicate plasticity or direct developmental relationships between DN, SP, and DP MPs.
Figure 2
Figure 2
Intestinal MPs play multiple non-immune roles to maintain tissue homeostasis. (A) Lymphoid tissue -associated MPs (lMPs) accumulate in PPs, ILFs and CPs. These lMPs sense and sample microbes and surround the B cell follicles within PPs and ILFs. Microbial recognition by lMPs facilitates the release of IL-1β and activates lymphoid tissue-resident group 3 innate lymphoid cells (ILC3s). ILC3s release CSF2 and IL-22 to engage CSF2R on myeloid cells or IL-22R on epithelial cells. The latter is prominent in facilitating antimicrobial activity. The former (CSF2-CSF2R) acts on DCs and lMPs to induce the production of IL-10 and RA, both critical in facilitating the conversion of naïve T cells in to regulatory T cells (Treg). Lymphoid tissue -associated MPs have also been shown to release the B cell-recruiting chemokine CXCL13 and clear apoptotic B cells resulting from failed somatic hypermutation or class-switch recombination, thus contributing to the local IgA response. (B) MPs lining the epithelium (eMPs) near intestinal crypts induce stem cell renewal by inducing WNT signaling in intestinal epithelial stem cells (IESC). Epithelium-associated MPs adopt an alternative activation phenotype when stimulated with by IL-4 and IL-13, by upregulating TREM-2 and aiding in epithelial repair and goblet cell proliferation. MPs in the subepithelial dome of the PPs have been shown to induce M cell maturation through the release of MIF. Hepatocyte growth factor (HGF) is another protein that mediates epithelial repair and is possibly produced by eMPs post injury with likely varying locations around the crypt and the villus. (C) Nerve-associated MPs (nMPs) in the intestinal muscularis layer are stimulated by the gut microbiota and regulate peristalsis via BMP2-mediated activation of enteric neurons. Enteric neurons release neurotransmitters to induce smooth muscle cell contractions. Direct activation of smooth muscle cell contraction is mediated by nMP-release of PGE2. In addition, nMPs release polyamines in response to signals from the microbiome, catecholamines, and other stress cues to facilitate neuronal protection. In turn, enteric neurons secrete CSF1 to support nMP survival. (D) Across the lamina propria, vasculature-associated MPs (vMPs) wrap around blood vessels to aid in angiogenesis, lipid transport, dead cell clearance, vessel integrity and elongation. In the presence of an intact microbiota, these MPs are rapidly replaced by monocyte-derived cells to induce vascular repair while protecting against bacterial dissemination upon injury and infection. How the endothelium in turn maintains MP survival is currently unknown. Vasculature-associated MPs in close proximity to small intestinal lacteals facilitate vessel elongation and integrity through the microbiota-driven production of VGEF-C.
Figure 3
Figure 3
The functional heterogeneity of intestinal MPs mirrors the multifaceted roles of tissue-resident MPs across organs. Intestinal MPs maintain tissue homeostasis through their interactions with neurons, immune cells, epithelial cells, and endothelial cells. These functions are dependent upon the associations with both immune and non-hematopoietic cells within their respective microenvironments. Released factors and physiological consequences of vasculature-associated MPs (vMPs, red), epithelium-associated MPs (eMPs, light brown), nerve-associated MPs (nMPs, light blue) and lymphoid tissue-associated MPs (lMPs, violet) are indicated by their respective colors. Arrows indicate the source of a given regulator (i.e. produced by MPs perceived by neighboring cell). Nerve-associated MPs in the brain, peripheral nervous system or the eye have specialized functions tailored to their location. These cells depend on neuron-released TGF-β, IL-34 and CSF1. Whether intestinal nMPs require the full spectrum of growth factors is unknown. In addition, a role for maintaining sensory neurons, neuronal growth or synaptic pruning in the gut remains to be shown. Lymphoid tissue-associated MPs are vital in antigen sampling, processing and presentation and mediate dead cell clearance of leukocytes within gut-associated lymphoid tissues. They contribute a plethora of cytokines, chemokines, metabolites and receptor ligands which plays an essential role in host defense against microbes, the orchestration of tolerance induction, and immune cell activation. CSF2, produced by T cells and ILC3s, is essential in facilitating most of these processes in the intestinal tract. It remains to be shown whether CSF1 or other myeloid growth factors like IL-10 support their biological relevance in intestinal immune homeostasis. Peripheral lymph node- and ILF-associated MPs mirror the function of lMPs in the gut, likely due to the similarities in the development and architecture of these organs. The thymus and BM, primary lymphoid tissues, host MPs that mediate tissue remodeling and control the hematopoietic stem cell egress, while also facilitating T cell maturation and clearance. Whether lMPs in the gut are capable of these functions remains to be addressed. The interactions of epithelium and MPs in the gut support IESC proliferation, maturation of secretory IEC and the repair the of damaged epithelial monolayer. CX3CL1 controls the adaptation of an eMPs phenotype but it remains to be shown if CSF1 or CSF2 produced by IECs in the gut contribute to this identity. In contrast to the gut, Keratinocytes, alveolar type 2 cells and urogenital epithelial cells produce distinct combinations of myeloid growth factors that facilitate development and functional specialization of MPs in their respective environments. In the case of the lung, WNT-release by lung macrophages mirrors the mechanism used by intestinal eMPs to facilitate epithelial repair. Functions of eMPs collectively promote tissue homeostasis and tissue remodeling. While the small intestinal lymphatic system is supported by vMPs through the production of VGEF-C to mediate vessel integrity and elongation, molecular mechanisms allowing for a deeper understanding of vMP-blood vessel interactions are currently not known for the intestinal tract. Vasculature-associated MPs surrounding intestinal blood vessel in a symmetric pattern that shields the endothelium from the environment, serving as a cellular firewall for the prevention of microbial spread into neighboring organs. Filter and barrier functions have been assigned to MPs in the spleen and the liver, where these cells are supported by endothelium-derived growth and differentiation factors. Cardiac MPs in fact receive survival signals from the endothelium via the release of CSF1 and in turn support the release of insulin growth factor (IGF) 1 and 2 as well as VGEF-A for cardiac remodeling and angiogenesis.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, et al. . Tissue-Resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment. Cell (2014) 159(6):1312–26. doi: 10.1016/j.cell.2014.11.018 - DOI - PMC - PubMed
    1. Cecchini MG, Dominguez MG, Mocci S, Wetterwald A, Felix R, Fleisch H, et al. . Role of Colony Stimulating Factor-1 in the Establishment and Regulation of Tissue Macrophages During Postnatal Development of the Mouse. Development (1994) 120(6):1357–72. doi: 10.1242/dev.120.6.1357 - DOI - PubMed
    1. Dai XM, Ryan GR, Hapel AJ, Dominguez MG, Russell RG, Kapp S, et al. . Targeted Disruption of the Mouse Colony-Stimulating Factor 1 Receptor Gene Results in Osteopetrosis, Mononuclear Phagocyte Deficiency, Increased Primitive Progenitor Cell Frequencies, and Reproductive Defects. Blood (2002) 99(1):111–20. doi: 10.1182/blood.V99.1.111 - DOI - PubMed
    1. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. . Fate Mapping Analysis Reveals That Adult Microglia Derive From Primitive Macrophages. Science (2010) 330(6005):841–5. doi: 10.1126/science.1194637 - DOI - PMC - PubMed
    1. Tauber AI. Metchnikoff and the Phagocytosis Theory. Nat Rev Mol Cell Biol (2003) 4(11):897–901. doi: 10.1038/nrm1244 - DOI - PubMed

Publication types

Grants and funding

LinkOut - more resources