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Gut immune cell trafficking: inter-organ communication and immune-mediated inflammation

Abstract

Immune cell trafficking is a complex and tightly regulated process that is indispensable for the body’s fight against pathogens. However, it is also increasingly acknowledged that dysregulation of cell trafficking contributes to the pathogenesis of immune-mediated inflammatory diseases (IMIDs) in gastroenterology and hepatology, such as inflammatory bowel disease and primary sclerosing cholangitis. Moreover, altered cell trafficking has also been implicated as a crucial step in the immunopathogenesis of other IMIDs, such as rheumatoid arthritis and multiple sclerosis. Over the past few years, a central role of the gut in mediating these disorders has progressively emerged, and the partly microbiota-driven imprinting of particular cell trafficking phenotypes in the intestine seems to be crucially involved. Therefore, this Review highlights achievements in understanding immune cell trafficking to, within and from the intestine and delineates its consequences for immune-mediated pathology along the gut–liver, gut–joint and gut–brain axes. We also discuss implications for current and future therapeutic approaches that specifically interfere with homing, retention, egress and recirculation of immune cells.

Key points

  • Immune-mediated inflammatory diseases (IMIDs) are a group of diseases with an important pathogenetic contribution of immune cell infiltration that depends on cell trafficking.

  • Sophisticated organ-specific mechanisms that regulate immune cell trafficking exist in the gut; however, re-routing cannot be precluded owing to pleiotropy and redundancy of the cell trafficking pathways.

  • Clinical and experimental observations established the gut as a central organ for several IMIDs of extra-intestinal organs and demonstrated disease-relevant communication via the gut–liver, gut–joint and gut–brain axes.

  • Cell trafficking mechanisms along these axes include the induction of pathogenic immune cells at the interface with the intestinal microbiome and their homing to extra-intestinal sites.

  • Anti-trafficking agents have been established for the treatment of inflammatory bowel disease and multiple sclerosis. The field is expected to grow further.

  • Gut-derived cell trafficking pathways in IMIDs represent an important yet insufficiently explored field for potential future therapeutic intervention.

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Fig. 1: Important immune-mediated inflammatory diseases, depicting examples of typical manifestation.
Fig. 2: Mechanisms of intestinal T cell trafficking.
Fig. 3: Key mechanisms of immune cell trafficking along the gut–liver, gut–joint and gut–brain axes.
Fig. 4: Overview of the mechanism of action of anti-trafficking agents.

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The authors thank the German Research Foundation for their funding (DFG, ZU 377/4-1, TRR241 A02, B08 and C04).

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M.F.N. has served as an adviser for Pentax, Giuliani, MSD, AbbVie, Janssen, Takeda and Boehringer. S.Z. received speaker’s fees from Takeda, Roche, Galapagos, Ferring, Lilly and Janssen. M.F.N. and S.Z. received research support from Takeda, Shire (a part of Takeda) and Roche. C.G., M.M.Z, V.R. and A.E.K. declare no conflicts of interest.

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Zundler, S., Günther, C., Kremer, A.E. et al. Gut immune cell trafficking: inter-organ communication and immune-mediated inflammation. Nat Rev Gastroenterol Hepatol (2022). https://doi.org/10.1038/s41575-022-00663-1

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