IL-38 Ameliorates Skin Inflammation and Limits IL-17 Production from γδ T Cells

Cell Rep. 2019 Apr 16;27(3):835-846.e5. doi: 10.1016/j.celrep.2019.03.082.


Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.

Keywords: IL-17; IL-38; IL1RAPL1; inflammation; psoriasis; γδ T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / therapeutic use
  • Cell Differentiation
  • Cytokines / metabolism
  • Disease Models, Animal
  • Humans
  • Imiquimod / toxicity
  • Inflammation / prevention & control
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism*
  • Interleukin-1 / pharmacology
  • Interleukin-1 Receptor Accessory Protein / deficiency
  • Interleukin-1 Receptor Accessory Protein / genetics
  • Interleukin-1 Receptor Accessory Protein / metabolism
  • Interleukin-17 / metabolism*
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Psoriasis / chemically induced
  • Psoriasis / pathology
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Regeneration / drug effects
  • Skin / metabolism
  • Skin / pathology*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*


  • Antibodies
  • Cytokines
  • Il1f10 protein, mouse
  • Interleukin-1
  • Interleukin-1 Receptor Accessory Protein
  • Interleukin-17
  • Receptors, Antigen, T-Cell, gamma-delta
  • interleukin-1 receptor accessory protein-like 1, mouse
  • Imiquimod