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 3

Excessive CXCL10 secreted by SPRY1-deficient keratinocytes promotes psoriatic arthritis–like inflammation.

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Excessive CXCL10 secreted by SPRY1-deficient keratinocytes promotes psor...
(A) Network of representative terms of all epidermal DEGs and all dermal DEGs (Spry1-cKO vs. control) commonly enriched by Metascape (P < 0.01). (B) Heatmap of top 10 upregulated chemokine genes in epidermis and dermis of Spry1-cKO mice (adjusted P < 0.05 and |log2FC| > 0.5, n = 3). (C–E) CXCL10 gene expression in human datasets: normal vs lesional epidermis (psoriasis, GSE166388); lesional vs nonlesional skin (PsA, GSE205748); and comparison across psoriasis, PsA, and ankylosing spondylitis (GSE186063). (F–H) ELISA quantification of CXCL10 in plasma, periarticular tissue, and epidermis of back skin from control and Spry1-cKO mice (n = 4). (I) Relative mRNA expression of Cxcl10 in mouse keratinocytes (n = 4). (J) Flow cytometric histograms and quantification of CXCL10 MFI of CD45–K14+ mouse keratinocytes (n = 4). (K) ELISA quantification of CXCL10 in supernatant of mouse keratinocytes (n = 4). (L) Immunoblotting analysis of protein levels associated with JAK1/2/STAT1 pathway in keratinocytes (left) or NHEKs transfected with siSPRY1 (right), both treated with 50 ng/mL recombinant IFN-γ for 24 hours (n = 3). ELISA quantification of CXCL10 in the supernatant of keratinocytes (n = 3). (M–P) Representative macroscopic views (M), H&E staining (scale bar: left, 500 μm; right, 250 μm) (N), Safranin O-Fast green staining (scale bar: 100 μm) (O), and TRAP staining (scale bar: 100 μm) (P) of paws from age- and sex-matched Spry1-cKO mice treated with anti-CXCL10 antibody and isotype antibody (IgG). Quantification shown below (n = 4). Data are shown as mean ± SEM. P values determined using 2-tailed unpaired Student’s t test (C, right panel of E and F–K, lower left panel of L, and M–P), 2-tailed paired Student’s t test (D, middle panel of E, lower right panel of L), and 1-way ANOVA (left panel of E). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.