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 6

Periarticular CD14hi macrophages aggravate psoriatic arthritis–like inflammation by producing TNF-α.

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Periarticular CD14hi macrophages aggravate psoriatic arthritis–like infl...
(A) Immunofluorescence staining of CD68 and CD14 in the digits from paws of control and Spry1-cKO mice. Boxed areas are magnified below. Scale bar: 50 μm. (B and C) Flow cytometric plots (B) and frequencies (C) of CD68+CD14hi macrophages, TNF-α+CD68+CD14hi macrophages, IL-1β+CD68+CD14hi macrophages, and CD68+CD14lo/– macrophages in the periarticular tissue from control and Spry1-cKO mice (n = 4). (D) Flow cytometric analysis of TNF-α, IL-1β, and CD86 expression in RAW264.7 cells treated with blank keratinocyte medium, control KC-CM, and Spry1-cKO KC-CM for 24 hours, followed by incubation with 50 ng/mL LPS and brefeldin A (a protein transport inhibitor) for 6 hours (n = 3). (E) Relative mRNA expression of genes associated with macrophage activation and polarization in RAW264.7 cells treated with blank KC medium, control KC-CM, and Spry1-cKO KC-CM for 24 hours (n = 3). (F–I) Representative macroscopic views (F), H&E staining (left scale bar: 500 μm; right scale bar: 250 μm) (G), Safranin O-Fast green staining (scale bar: 100 μm) (H), and TRAP staining (scale bar: 100 μm) (I) of the paws from age- and sex-matched Spry1-cKO mice treated with anti-CD14 antibody and isotype antibody (IgG). Lower panels show quantification of arthritis scores, total histological scores, Safranin-O intensity, and TRAP+ osteoclasts, respectively (n = 4). Data are shown as mean ± SEM. P values were determined using 2-tailed unpaired Student’s t test (C and F–I) and 1-way ANOVA (D and E). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.