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Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis.

Author information

Affiliations

  • 1. Department of Microbiology & Immunology, Columbia University, New York, NY, USA.
      Authors
    • Savage TM 1
    • Fortson KT 1
    • de Los Santos-Alexis K 1
    • Oliveras-Alsina A 1
    • Rouanne M 1
    • Rae SS 1
    • Cavero R 1
    • Li F 1
    (8 authors)
  • 2. Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA.
      Authors
    • Gamarra JR 2
    (1 author)
  • 3. Mortimer B. Zuckerman Mind, and Brain and Behavior Institute, Columbia University, New York, NY, USA.
      Authors
    • Shayya H 3
    (1 author)
  • 4. Department of Microbiology & Immunology, Columbia University, New York, NY, USA; Columbia Center for Translational Immunology, Columbia University, New York, NY, USA.
      Authors
    • Kornberg A 4
    (1 author)
  • 5. Department of Microbiology & Immunology, Columbia University, New York, NY, USA; Columbia Center for Translational Immunology, Columbia University, New York, NY, USA; Department of Medicine, Columbia University, New York, NY, USA.
      Authors
    • Han A 5
    (1 author)
    • Show all (9)

Immunity, 02 Feb 2024, 57(2):303-318.e6
https://doi.org/10.1016/j.immuni.2024.01.009 PMID: 38309273 

Free full text available after 13 Feb 2025

Abstract 

Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.

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Read article at publisher's site: https://doi.org/10.1016/j.immuni.2024.01.009

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