Macrophages
Given the potential threats faced by your gut in terms of exposure to bugs, it is not surprising that there is an immune ‘border force’ in place to ensure that any intruder is swiftly dealt with. Macrophages form part of this border force. Their name comes from the Greek for ‘big eater’ (makros = large, phagein = to eat), and they do just that in every tissue of the body. In the gut, these cells are strategically positioned to detect, capture and destroy any bugs that pass through the exterior/structural barrier. Importantly, they can do this without triggering an inflammatory response – something that could lead to pain and unnecessary damage to the gut tissue. If the infection or challenge is too much for these cells alone, macrophages call in reinforcements through producing specific chemical signals.
As well as acting as a vital part of the border force, macrophages can be thought of as being part of the house keeping team. This is necessary to deal with the general ‘wear and tear’ that occurs in each of our tissues. It is estimated that 50-70 billion of our cells die each day and are replaced with new cells to keep tissues healthy – the structural barrier of the gut represents one of the most highly replaced parts of our body. Macrophages play a vital role in cleaning up these dying cells and recycling some of their parts.
But it would be wrong to think of macrophages simply as waste disposal units. They also produce signals that keep other cells within the gut alive, and they orchestrate any repair following infection or inflammation. Because of these multi-faceted roles, when macrophages become dysregulated (the reasons for which are not clear), they can contribute to diseases such as inflammatory bowel disease, where parts of the gut become inflamed, causing pain and distress.
Expert information on macrophages
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The last 15-20 years has seen many of the paradigms surrounding macrophage biology rewritten. From heterogeneity and ontogeny to non-canonical functions, macrophages have moved well beyond their reputations as simple scavengers.
Advances in single cell and spatial technologies have shown that all tissues have a diverse macrophage compartment, with the identity and function of these cells dictated by the microanatomical niche they occupy. Moreover, these technologies have allowed for much more meaningful and accurate cross-species analysis to be carried out, thereby allowing human macrophages and their correlates in pre-clinical models to be compared (Jones et al., 2024). Strategies to categorise macrophages have changed considerably, with simplified concepts such as the ‘M1 vs. M2’ classification rendered somewhat obsolete in the ‘OMICs’ era.
Macrophages are crucial for eliciting responses against enteric pathogens, with their depletion altering bacterial burden and T cell responses to Citrobacter rodentium, a murine model of E. coli infection (Schreiber et al., 2013). However, macrophages are diverse along and throughout the gut wall, with those present in the mucosa, submucosa and deeper muscularis displaying differences in their identity, transcriptome and replenishment kinetics (Hegarty et al., 2023). Mucosal macrophages, including those in the subepithelial niche, are enriched in trophic factors such as Wnt ligands, hepatocyte growth factor and prostaglandin E2, that promote epithelial stem cell renewal and integrity. This regulation is key as apoptotic epithelial cells accumulate in the gut of mice with targeted deletion of machinery required for apoptotic cell uptake (Lacy-Hulbert et al., 2007). Mucosal macrophages are also rich sources of vascular endothelial growth factor (VEGF) that maintains vascular endothelial structures (Honda et al., 2020).
Macrophages in the deeper layers of the gut wall, including the submucosa and muscularis, are often associated with nerves. There is thought to be vital bidirectional crosstalk mediated by bone morphogenetic protein 2 (BMP2) and colony stimulating factor 1 (CSF-1) between these macrophages and nerves, which aids physiological processes such as peristalsis (Muller et al., 2014).
The interaction with different cell types and/or their products in discrete anatomical locales likely drives the differences in the functional profile of associated macrophages, but also their longevity. Macrophages in the mucosa show high levels of replenishment from monocytes relative to their counterparts in the deeper layers of the gut wall but also compared with macrophages in other tissues. (Hegarty et al., 2026). The exact reasons for this remain poorly understood but may reflect the proximity to the vast and diverse microbiota and/or the highly dynamic epithelial barrier, which undergoes complete remodelling every 3-5 days.
Despite carrying out these crucial homeostatic and immune functions, intestinal macrophages are also implicated in the pathogenesis of chronic inflammatory conditions of the gastrointestinal tract, including inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis. Single cell and spatial analysis increasingly places macrophages at the centre of IBD inflammation (Fenton et al., 2025; Garrido-Trigo et al., 2023; Jones et al., 2024). These analyses are uncovering unappreciated heterogeneity in intestinal macrophages, demonstrating that inflammation-associated macrophages appear to be distinct from their homeostatic counterparts, and may even arise from distinct circulating progenitors (Jones et al., 2024).
Text by Calum Bain, University of Glasgow
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https://doi.org/10.1038/s41575-023-00769-0
Hegarty, L.M., Jones, G.-R., Biram, A., Adams, C.E., Gentek, R.M., Ho, G.-T., Emmerson, E., Bain, C.C., 2026. Tissue resident colonic macrophages persist through acute inflammation and adapt to aid tissue repair. Mucosal Immunol 19, 1624–1635.
https://doi.org/10.1016/j.mucimm.2025.11.007
Honda, M., Surewaard, B.G.J., Watanabe, M., Hedrick, C.C., Lee, W.-Y., Brown, K., McCoy, K.D., Kubes, P., 2020. Perivascular localization of macrophages in the intestinal mucosa is regulated by Nr4a1 and the microbiome. Nat Commun 11, 1329.
https://doi.org/10.1038/s41467-020-15068-4
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https://doi.org/10.1101/2024.11.15.623347
Lacy-Hulbert, A., Smith, A.M., Tissire, H., Barry, M., Crowley, D., Bronson, R.T., Roes, J.T., Savill, J.S., Hynes, R.O., 2007. Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins. Proc Natl Acad Sci U S A 104, 15823–15828.
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