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Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD

Abstract

Macrophages are the gatekeepers of intestinal immune homeostasis as they discriminate between innocuous antigens and potential pathogens to maintain oral tolerance. However, in individuals with a genetic and environmental predisposition, regulation of intestinal immunity is impaired, leading to chronic relapsing immune activation and pathologies of the gastrointestinal tract, such as IBD. As evidence suggests a causal link between defects in the resolution of intestinal inflammation and altered monocyte–macrophage differentiation in patients with IBD, macrophages have been considered as a novel potential target to develop new treatment approaches. This Review discusses the molecular and cellular mechanisms involved in the differentiation and function of intestinal macrophages in homeostasis and inflammation, and their role in resolving the inflammatory process. Understanding the molecular pathways involved in the specification of intestinal macrophages might lead to a new class of targets that promote remission in patients with IBD.

Key points

  • Intestinal macrophages have roles in maintaining tissue homeostasis, in inflammation, and especially in inducing resolution after inflammation.

  • Resolution of inflammation in general is an active process controlled by local recruitment of monocytes and accumulation of alternatively activated macrophages with proresolving capacity.

  • Resolution of intestinal inflammation and mucosal healing is a pivotal step for complete remission of IBD.

  • Findings suggest a causal link between IBD and defects in the transition of monocytes to proresolving macrophages, as exemplified by successful IBD therapies that favour alternatively activated macrophage differentiation.

  • A deeper understanding of the molecular pathways involved in the differentiation and functions of intestinal macrophages might lead to a new class of targets to promote remission in patients with IBD.

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Fig. 1: Differentiation and function of intestinal macrophages in homeostasis.
Fig. 2: Macrophages in intestinal inflammation and resolution.
Fig. 3: Alteration of macrophages in a patient with IBD.
Fig. 4: Current and future macrophage-directed IBD therapeutics.

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Acknowledgements

G.M. and S.H.S. are supported by the cooperation grant VS03917N between the Research Foundation — Flanders (FWO, Belgium) and the National Research Foundation of Korea (NRF, South Korea). G.M. is also supported by an FWO grant (G.0D83.17N), a grant from the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD), a grant from the European Crohn´s and Colitis Organization (ECCO) and grants from the KU Leuven Internal Funds (C12/15/016 and C14/17/097). Y.R.N. was supported by the Basic Science Research Program through the NRF, funded by the Ministry of Science, ICT and Future Planning (NRF-2017R1D1A1B04031161). S.H.S. was supported by the Promising–Pioneering Researcher Program through Seoul National University (South Korea). M.S. is supported by an FWO PhD fellowship.

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Na, Y.R., Stakenborg, M., Seok, S.H. et al. Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nat Rev Gastroenterol Hepatol 16, 531–543 (2019). https://doi.org/10.1038/s41575-019-0172-4

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