JCI Insight (Mar 2023)

The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease

  • Erica Dander,
  • Paola Vinci,
  • Stefania Vetrano,
  • Camilla Recordati,
  • Rocco Piazza,
  • Grazia Fazio,
  • Donatella Bardelli,
  • Mattia Bugatti,
  • Francesca Sozio,
  • Andrea Piontini,
  • Sonia Bonanomi,
  • Luca Bertola,
  • Elena Tassistro,
  • Maria Grazia Valsecchi,
  • Stefano Calza,
  • William Vermi,
  • Andrea Biondi,
  • Annalisa Del Prete,
  • Silvano Sozzani,
  • Giovanna D’Amico

Journal volume & issue
Vol. 8, no. 5

Abstract

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Gastrointestinal graft-versus-host disease (GvHD) is a major cause of mortality and morbidity following allogeneic bone marrow transplantation (allo-BMT). Chemerin is a chemotactic protein that recruits leukocytes to inflamed tissues by interacting with ChemR23/CMKLR1, a chemotactic receptor expressed by leukocytes, including macrophages. During acute GvHD, chemerin plasma levels were strongly increased in allo-BM-transplanted mice. The role of the chemerin/CMKLR1 axis in GvHD was investigated using Cmklr1-KO mice. WT mice transplanted with an allogeneic graft from Cmklr1-KO donors (t-KO) had worse survival and more severe GvHD. Histological analysis demonstrated that the gastrointestinal tract was the organ mostly affected by GvHD in t-KO mice. The severe colitis of t-KO mice was characterized by massive neutrophil infiltration and tissue damage associated with bacterial translocation and exacerbated inflammation. Similarly, Cmklr1-KO recipient mice showed increased intestinal pathology in both allogeneic transplant and dextran sulfate sodium–induced colitis. Notably, the adoptive transfer of WT monocytes into t-KO mice mitigated GvHD manifestations by decreasing gut inflammation and T cell activation. In patients, higher chemerin serum levels were predictive of GvHD development. Overall, these results suggest that CMKLR1/chemerin may be a protective pathway for the control of intestinal inflammation and tissue damage in GvHD.

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