Unprocessed Interleukin-36α Regulates Psoriasis-Like Skin Inflammation in Cooperation With Interleukin-1

J Invest Dermatol. 2015 Dec;135(12):2992-3000. doi: 10.1038/jid.2015.289. Epub 2015 Jul 23.

Abstract

Generalized pustular psoriasis is a severe skin disease characterized by epidermal hyperplasia, neutrophil-rich abscesses within the epidermis, and a mixed inflammatory infiltrate in the dermis. The disease may be caused by missense mutations in the IL-36 receptor antagonist, IL-36Ra. Curiously, the related IL-1Ra has therapeutic effects in some of these latter patients. Here, using an experimental mouse model of psoriasiform skin inflammation, we demonstrate in vivo connections between IL-36 and IL-1 expression. After disease initiation, IL-36α-deficient mice exhibited dramatically diminished skin pathology, including absence of epidermal neutrophils, reduced keratinocyte acanthosis, and less dermal edema. In contrast, IL-36β and IL-36γ knockout mice developed disease indistinguishable from that of wild-type mice. The endogenous IL-36α was not processed through proteolysis. Although IL-36α expression was strongly induced in an IL-1 signaling-dependent manner during disease, expression of IL-1α was also dependent upon IL-36α. Hence, after being upregulated by IL-1α, IL-36α acts through a feedback mechanism to boost IL-1α levels. Analyses of double knockout mice further revealed that IL-36α and IL-1α cooperate to promote psoriasis-like disease. In conclusion, IL-1α and IL-36α form a self-amplifying inflammatory loop in vivo that in patients with insufficient counter regulatory mechanisms may become hyper-engaged and/or chronic.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abscess / etiology
  • Animals
  • Cell Movement
  • Cells, Cultured
  • Chemokine CXCL1 / physiology
  • Dermatitis / etiology*
  • Dermatitis / immunology
  • Epidermis / pathology
  • Humans
  • Interleukin-1 / physiology*
  • Interleukin-17 / physiology
  • Interleukin-1alpha / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / physiology
  • Psoriasis / etiology*
  • Psoriasis / immunology

Substances

  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • Interleukin-1
  • Interleukin-17
  • Interleukin-1alpha
  • interleukin 1F6, mouse