CXCR4 negatively regulates keratinocyte proliferation in IL-23-mediated psoriasiform dermatitis

CXCR4 is expressed by basal keratinocytes (KCs), but little is known about its function in inflamed skin. We crossed K14-Cre and CXCR4(flox/flox (f/f)) transgenic mice, resulting in mice with specific loss of the CXCR4 gene in K14-expressing cells (K14-CXCR4KO), including basal KCs. K14-CXCR4KO pups had no obvious skin defects. We compared K14-CXCR4KO and CXCR4(f/f) control mice in an IL-23-mediated psoriasisform dermatitis model and measured skin edema, histologic, and immunohistological changes. IL-23-treated K14-CXCR4KO mice showed a 1.3-fold increase in mean ear swelling, 2-fold increase in epidermal thickness, and greater parakeratosis. IL-23-treated WT mice showed weak CXCR4 expression in areas of severe epidermal hyperplasia, but strong CXCR4 expression in non-hyperplastic regions, suggesting CXCR4 may regulate keratinocyte proliferation. To test this hypothesis, we overexpressed CXCR4 in HaCaT keratinocyte cells and treated them with IL-22 and/or CXCL12. CXCL12 blocked IL-22-mediated HaCaT cell proliferation in vitro and synergized with IL-22 in upregulating SOCS3, a key regulator of STAT3. SOCS3 was required for CXCR4-mediated growth inhibition. In human psoriatic skin, both CXCR4 and SOCS3 were upregulated in the junctional region at the border of psoriatic plaques. Thus, CXCR4 plays an unexpected role in inhibiting KC proliferation and mitigating the effects of proliferative Th17 cytokines.