IBD macrophages beyond the M1/M2 divide: targets for immunomodulatory and regenerative therapies
Background: Macrophages regulate inflammation and tissue repair
Macrophages in inflammatory bowel disease (IBD) display diversity and plasticity that are difficult to explain with only two categories: pro-inflammatory and anti-inflammatory. A review published in International Immunopharmacology summarizes these properties and examines therapeutic strategies aimed at immune regulation and tissue regeneration. It discusses macrophage roles and directions for therapeutic development based on existing research.
IBD, which mainly includes Crohn’s disease and ulcerative colitis, is a chronic condition involving recurrent intestinal inflammation. Genetic predisposition, gut microbial imbalance, epithelial barrier damage, and abnormal immune activation contribute to its development. Macrophages, which regulate intestinal immune homeostasis, have therefore attracted considerable research interest. Their roles extend beyond inflammatory responses. They also participate in tissue remodeling and mucosal repair, and their functional states change in response to signals from their surroundings. This capacity to change is called plasticity.
Key findings: Functional diversity beyond two categories and therapeutic approaches
The traditional classification divides macrophages into pro-inflammatory M1 and anti-inflammatory M2 types. However, recent single-cell transcriptomic and spatial analyses discussed in the review suggest that intestinal macrophages form a more diverse and dynamic population. The review describes multiple macrophage subtypes coexisting in the intestinal microenvironment, with inflammatory, regulatory, reparative, and fibrosis-related functions. These subtypes contribute in different ways to disease progression and tissue healing.
Therapeutic research considers selective approaches that account for these differences. The review examines strategies involving the cells themselves, including macrophage transfer into the body, functionally engineered macrophages, and gene editing. Receptor-targeted therapies and nanoparticle-based drug delivery are also covered. However, the available abstract makes it difficult to compare the experimental conditions or effects of these strategies quantitatively.
The review also discusses approaches that modify the intestinal environment to which macrophages respond. These include modulation of the gut microbiota and microbial metabolites; organoid technologies and biomaterial-assisted platforms are also considered. Alongside these therapeutic approaches, the authors discuss macrophage contributions to epithelial regeneration, mucosal healing, fibrosis, and intestinal tissue remodeling. The abstract does not present experimental results showing that a specific platform controlled these functions simultaneously.
Implications and outlook: Potential for precision therapies and outstanding validation needs
The review’s central message is that a better understanding of macrophage functional diversity and changes in response to the environment provides a foundation for developing selective targeted therapies. This perspective considers mucosal recovery and tissue remodeling alongside inflammation control. The authors suggest that advances in immunology, regenerative medicine, microbiome research, and biomaterials science could support the development of precision and personalized therapies for patients with IBD.
At the same time, the authors state that major challenges continue to limit the clinical translation of macrophage-targeted therapies. The available abstract does not specify those challenges or provide the clinical phase, patient numbers, effect sizes, or follow-up periods for individual therapies. It is therefore difficult to determine from this material alone whether treatments can be assigned to individual patients based on specific subtypes or whether mucosal healing rates can be improved. This review can be read as a starting point for considering how macrophage functional diversity might inform therapeutic research.
Sources: Europe PMC abstract and bibliographic information, article DOI.
Inflammatory bowel disease (IBD), which mainly includes Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract characterized by recurrent episodes of intestinal inflammation. The development of IBD is influenced by multiple factors, including genetic predisposition, intestinal dysbiosis, epithelial barrier impairment, and abnormal immune activation. Among innate immune cells, macrophages are key regulators of intestinal immune homeostasis and are involved in inflammatory responses, tissue remodeling, and mucosal repair. Their ability to adopt different functional states in response to local environmental signals has made them an important focus of current therapeutic research in IBD. Traditionally, macrophages have been classified into pro-inflammatory M1 and anti-inflammatory M2 phenotypes. However, recent findings from single-cell transcriptomic and spatial analyses suggest that intestinal macrophages represent a far more diverse and dynamic population than this simplified classification implies. Multiple macrophage subsets with inflammatory, regulatory, reparative, and fibrosis-associated functions coexist within the intestinal microenvironment and contribute differently to disease progression and tissue healing. These observations highlight the importance of developing more selective and targeted macrophage-based therapeutic approaches. In this review, we discuss the current understanding of macrophage plasticity and its role in the pathogenesis of IBD. Particular attention is given to newer macrophage-targeted therapeutic strategies, including adoptive macrophage transfer, engineered macrophages, receptor-targeted therapies, nanoparticle-based delivery systems, microbiome modulation, microbial metabolite regulation, gene-editing approaches, organoid technologies, and biomaterial-assisted platforms. We also examine the contribution of macrophages to epithelial regeneration, mucosal healing, fibrosis, and intestinal
In IBD treatment research, it can be useful to distinguish macrophage functions in inflammation control and tissue repair rather than classify them only as pro-inflammatory or anti-inflammatory. For example, a team studying mucosal recovery could consider the cell-based approaches, drug delivery, and microbiota modulation discussed in the review as candidates for further validation. It could also assess whether organoid or biomaterial platforms fit its research question. This is a research-design scenario drawing on the review’s discussion; it does not mean that any approach has been shown to be superior or therapeutically effective. Applying these ideas to treatment choices for individual patients would require separate review of the populations, conditions, and endpoints in the original studies, as well as the clinical evidence.