Spread of Psoriasiform Inflammation to Remote Tissues Is Restricted by the Atypical Chemokine Receptor ACKR2

详细信息    查看全文

• 作者：Kave Shams¹ ; Gillian J. Wilson¹ ; Mark Singh¹ ; Ellen H. van den Bogaard² ; Michelle L. Le Brocq¹ ; Susan Holmes³ ; Joost Schalkwijk² ; A. David Burden¹ ; ⁴ ; Clive S. McKimmie¹ ; ⁵ ; ⁶ ; ^{c.s.mckimmie@leeds.ac.uk} ; Gerard J. Graham¹ ; ⁶ ; ^{gerard.graham@glasgow.ac.uk}
• 关键词：ACKR2 ; atypical chemokine receptor 2 ; IMQ ; imiquimod ; PASI ; Psoriasis Area Severity Index ; WT ; wild type
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：137
• 期：1
• 页码：85-94
• 全文大小：4013 K
• 卷排序：137

文摘

Elucidating the poorly defined mechanisms by which inflammatory lesions are spatially restricted in vivo is of critical importance in understanding skin disease. Chemokines are the principal regulators of leukocyte migration and are essential in the initiation and maintenance of inflammation. The membrane-bound psoriasis-associated atypical chemokine receptor 2 (ACKR2) binds, internalizes and degrades most proinflammatory CC-chemokines. Here we investigate the role of ACKR2 in limiting the spread of cutaneous psoriasiform inflammation to sites that are remote from the primary lesion. Circulating factors capable of regulating ACKR2 function at remote sites were identified and examined using a combination of clinical samples, relevant primary human cell cultures, in vitro migration assays, and the imiquimod-induced model of psoriasiform skin inflammation. Localized inflammation and IFN-γ together up-regulate ACKR2 in remote tissues, protecting them from the spread of inflammation. ACKR2 controls inflammatory T-cell chemotaxis and positioning within the skin, preventing an epidermal influx that is associated with lesion development. Our results have important implications for our understanding of how spatial restriction is imposed on the spread of inflammatory lesions and highlight systemic ACKR2 induction as a therapeutic strategy in the treatment and prevention of psoriasis and potentially a broad range of other immune-mediated diseases.