4.7 Article

Activation of the C3a anaphylatoxin receptor inhibits keratinocyte proliferation by regulating keratin 6, keratin 16, and keratin 17 in psoriasis

期刊

FASEB JOURNAL
卷 36, 期 5, 页码 -

出版社

WILEY
DOI: 10.1096/fj.202101458R

关键词

C3a anaphylatoxin receptor; complement; downregulation; keratin; proliferation; psoriasis

资金

  1. National Natural Science Foundation of China [82173411, 82030096, 81972929, 81903206]

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Studies have shown that C3aR plays a protective role in psoriasis by negatively regulating the expression of K6, K16, and K17 in keratinocytes to inhibit cell proliferation and help reverse the progression of the disease.
Emerging evidence suggests that signaling through the C3a anaphylatoxin receptor (C3aR) protects against various inflammation-related diseases. However, the role of C3aR in psoriasis remains unknown. The purpose of this study was to investigate the possible protective role of C3aR in psoriasis and to explore the underlying molecular mechanisms. We initially found that the psoriatic epidermis exhibited significantly decreased C3aR expression. C3aR showed protective roles in mouse models of imiquimod (IMQ)- and interleukin-23-induced psoriasis. Furthermore, increased epidermal thickness and keratin 6 (K6), K16, and K17 expression occurred in the ears and backs of C3aR(-/-) mice. Pharmacological treatment with a C3aR agonist ameliorated IMQ-induced psoriasiform lesions in mice and decreased the expression of K6, K16, and K17. Additionally, the signal transducer and activator of transcription 3 (STAT3) pathway participated in the protective function of C3aR. More importantly, the expression levels of K6, K16, and K17 in keratinocytes were all restored in HaCaT cells transfected with a C3aR-overexpression plasmid after treating them with colivelin (a STAT3 activator). Our findings demonstrate that C3aR protects against the development of psoriasis and suggest that C3aR confers protection by negatively regulating K6, K16, and K17 expression in a STAT3-dependent manner, thus inhibiting keratinocyte proliferation and helping reverse the pathogenesis of psoriasis.

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