CXCL10 secreted by SPRY1-deficient epidermal keratinocytes fuels joint inflammation in psoriatic arthritis via CD14 signaling
Fan Xu, Ying-Zhe Cui, Xing-Yu Yang, Yu-Xin Zheng, Xi-Bei Chen, Hao Zhou, Zhao-Yuan Wang, Yuan Zhou, Yi Lu, Ying-Ying Li, Li-Ran Ye, Ni-Chang Fu, Si-Qi Chen, Xue-Yan Chen, Min Zheng, Yong Yang, Xiao-Yong Man
Fan Xu, Ying-Zhe Cui, Xing-Yu Yang, Yu-Xin Zheng, Xi-Bei Chen, Hao Zhou, Zhao-Yuan Wang, Yuan Zhou, Yi Lu, Ying-Ying Li, Li-Ran Ye, Ni-Chang Fu, Si-Qi Chen, Xue-Yan Chen, Min Zheng, Yong Yang, Xiao-Yong Man
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Research Article Dermatology Immunology

CXCL10 secreted by SPRY1-deficient epidermal keratinocytes fuels joint inflammation in psoriatic arthritis via CD14 signaling

Abstract

Psoriatic arthritis (PsA) is a multifaceted, chronic inflammatory disease affecting the skin, joints, and entheses, and it is a major comorbidity of psoriasis. Most patients with PsA present with psoriasis before articular involvement; however, the molecular and cellular mechanisms underlying the link between cutaneous psoriasis and PsA are poorly understood. Here, we found that epidermis-specific SPRY1-deficient mice spontaneously developed PsA-like inflammation involving both the skin and joints. Excessive CXCL10 was secreted by SPRY1-deficient epidermal keratinocytes through enhanced activation of JAK1/2/STAT1 signaling, and CXCL10 blockade attenuated PsA-like inflammation. Of note, CXCL10 was found to bind to CD14, but not CXCR3, to promote the TNF-α production of periarticular CD14hi macrophages via PI3K/AKT and NF-κB signaling pathways. Collectively, this study reveals that SPRY1 deficiency in the epidermis is sufficient to drive both skin and joint inflammation, and it identifies keratinocyte-derived CXCL10 and periarticular CD14hi macrophages as critical links in the skin-joint crosstalk leading to PsA. This keratinocyte SPRY1/CXCL10/periarticular CD14hi macrophage/TNF-α axis provides valuable insights into the mechanisms underlying the transition from psoriasis to PsA and suggests potential therapeutic targets for preventing this progression.

Authors

Fan Xu, Ying-Zhe Cui, Xing-Yu Yang, Yu-Xin Zheng, Xi-Bei Chen, Hao Zhou, Zhao-Yuan Wang, Yuan Zhou, Yi Lu, Ying-Ying Li, Li-Ran Ye, Ni-Chang Fu, Si-Qi Chen, Xue-Yan Chen, Min Zheng, Yong Yang, Xiao-Yong Man

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Figure 1

Epidermis-specific SPRY1-deficient mice spontaneously develop psoriasis-like skin lesions and arthritis.

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Epidermis-specific SPRY1-deficient mice spontaneously develop psoriasis-...
(A) Macroscopic views of the ears, shaved back skin, and paws from control and Spry1-cKO mice. (B) Ear and back skin thickness; PASI scores of back skin; digit, and paw thickness; and arthritis scores of control and Spry1-cKO mice (n = 6). (C) Incidence of inflammation in ears, back skin, and paws of control and Spry1-cKO mice after tamoxifen treatment (n = 20). (D) SPRY1 gene expression in lesional and nonlesional skin from patients with PsA from the NCBI’s GEO database (GSE205748). (E) SPRY1 gene expression in lesional and nonlesional skin from patients with psoriasis or PsA, and normal skin from patients with ankylosing spondylitis from the GEO database (GSE186063). (F and G) Representative H&E staining of the back skin and ears of control and Spry1-cKO mice. Lower panels show quantification of epidermis thickness respectively (n = 6). Scale bar: 100 μm. (H–K) Representative H&E staining of the digits from paws of control and Spry1-cKO mice (H), scale bar: 500 μm. Boxed areas magnified in (I–K) are the following: epidermal hyperplasia (I), fibroplasia (J), and inflammatory infiltrate (K), black arrows indicate enthesitis, scale bar: 250 μm. Lower panels show histological scores (n = 6). Data are shown as mean ± SEM. P values were determined using 2-tailed unpaired Student’s t test (B, the right panel of E, and F–K), 2-tailed paired Student’s t test (D and the middle panel of E), and 1-way ANOVA (the left panel of E). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.