Efficacy of Chemokine Receptor Inhibition in Treating IL-36α–Induced Psoriasiform Inflammation

Abstract

Several types of psoriasiform dermatitis are associated with increased IL-36 cytokine activity in the skin. A rare, but severe, psoriasis-like disorder, generalized pustular psoriasis (GPP), is linked to loss-of-function mutations in the gene encoding IL-36RA, an important negative regulator of IL-36 signaling. To understand the effects of IL-36 dysregulation in a mouse model, we studied skin inflammation induced by intradermal injections of preactivated IL-36α. We found the immune cells infiltrating IL-36α–injected mouse skin to be of dramatically different composition than those infiltrating imiquimod-treated skin. The IL-36α–induced leukocyte population comprised nearly equal numbers of CD4+ αβ T cells, neutrophils, and inflammatory dendritic cells, whereas the imiquimod-induced population comprised γδ T cells and neutrophils. Ligands for chemokine receptors CCR6 and CXCR2 are increased in both GPP and IL-36α–treated skin, which led us to test an optimized small-molecule antagonist (CCX624) targeting CCR6 and CXCR2 in the IL-36α model. CCX624 significantly reduced the T cell, neutrophil, and inflammatory dendritic cell infiltrates and was more effective than saturating levels of an anti–IL-17RA mAb at reducing inflammatory symptoms. These findings put CCR6 and CXCR2 forward as novel targets for a mechanistically distinct therapeutic approach for inflammatory skin diseases involving dysregulated IL-36 signaling, such as GPP.

Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation

“…Previous studies revealed an important contribution of keratinocyte-derived CXCL1 and CXCL2 to the development of psoriasis, as these chemokines trigger the infiltration of neutrophils into the skin (30). In agreement, blocking of the CXCR2 receptor using a small-molecule antagonist efficiently blocked IL-36-driven skin inflammation (31). Similarly, we found that neutrophil and macrophage especially infiltration was absent in IMQ-or IL-36treated K14-Cre Nfkbiz-KO mice, along with a lack of expression of Cxcl1, Cxcl2, or Cxcl5.…”

Interleukin-17A and Keratinocytes in Psoriasis

“…Preclinical studies have revealed that the humanized anti-CCR6 antibody efficiently inhibits the cutaneous infiltration of CCR6 + T cells in human and murine models [205,206]. The development of small molecule inhibitors against CCR6 is also ongoing [207,208]. Targeting the CCL20/CCR6 axis may be a potential therapeutic strategy for the treatment of psoriasis.…”

The CCL20 and CCR6 axis in psoriasis

“…In addition, preclinical study reveals that humanized anti‐CCR6 antibody efficiently inhibits the imiquimod‐induced psoriasiform dermatitis in human CCR6 ‐transgenic/mouse Ccr6 ‐deficient mice . Development of small molecule inhibitors against CCR6 is also ongoing . CCX624 is a potent antagonist for CCR6 and CXCR2 .…”

“…75 Development of small molecule inhibitors against CCR6 is also ongoing. 76,77 CCX624 is a potent antagonist for CCR6 and CXCR2. 77 Administration of CCX624 significantly alleviates the imiquimod-induced and IL-36α-induced murine psoriasiform inflammation by inhibiting intralesional infiltration of CCR6+ T cells and dendritic cells as well as CXCR2+ neutrophils.…”

“…76,77 CCX624 is a potent antagonist for CCR6 and CXCR2. 77 Administration of CCX624 significantly alleviates the imiquimod-induced and IL-36α-induced murine psoriasiform inflammation by inhibiting intralesional infiltration of CCR6+ T cells and dendritic cells as well as CXCR2+ neutrophils. 77 These preclinical studies reinforces the crucial role of CCL20-CCR6 axis in the pathogenesis of psoriasis.…”