Dupuytren’s contracture-associated SNPs increase SFRP4 expression in non-immune cells including fibroblasts to enhance inflammation development

• Published in: International immunology 2023-07, Vol.35 (7), p.303-312
• Main Authors: Kida, Hiroaki, Jiang, Jing-Jing, Matsui, Yuichiro, Takahashi, Ikuko, Hasebe, Rie, Kawamura, Daisuke, Endo, Takeshi, Shibayama, Hiroki, Kondo, Makoto, Nishio, Yasuhiko, Nishida, Kinya, Matsuno, Yoshihiro, Oikawa, Tsukasa, Kubota, Shimpei I, Hojyo, Shintaro, Iwasaki, Norimasa, Hashimoto, Shigeru, Tanaka, Yuki, Murakami, Masaaki
• Format: Article
• Language: English
• Subjects: Dupuytren Contracture - genetics; Dupuytren Contracture - pathology; Fibroblasts - metabolism; Genome-Wide Association Study; Humans; Inflammation - genetics; Inflammation - metabolism; Interleukin-6 - metabolism; NF-kappa B - metabolism; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins - metabolism
• ISSN: 1460-2377; 1460-2377
• DOI: 10.1093/intimm/dxad004

Abstract Dupuytren’s contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and βTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC. SFRP4 activates NF- B in Dupuytren’s contracture Graphical Abstract