Suppression of TCF4 promotes a ZC3H12A-mediated self-sustaining inflammatory feedback cycle involving IL-17RA/IL-17RE epidermal signaling

• DOI: 10.1172/jci.insight.172764
• Publication Date: 2024-04-23T14:22:17Z
• Authors: Yanyun Jiang; Dennis Gruszka; Chang Zeng; William R. Swindell; Christa Gaskill; Christian Sorensen; Whitney Brown; Roopesh Singh Gan...; Lam C. Tsoi; Joshua Webster; Sigrún Laufey Sig...; Mrinal K. Sarkar; Ranjitha Uppala; Austin Kidder; Xianying Xing; Olesya Plazyo; Enze Xing; Allison C. Billi; Emanual Maverakis; J. Michelle Kahle...; Johann E. Gudjonsson; Nicole L. Ward
• Keywords: Keratinocytes; Physiological; Immunology; 610; Dermatitis; Dermatology; Signal transduction; Feedback; Mice; Transcription Factor 4; Ribonucleases; Receptors; Animals; Humans; Skin; Adaptor Proteins, Signal Transducing; Inflammation; Feedback, Physiological; Receptors, Interleukin-17; Animal; Interleukin-17; Signal Transducing; Adaptor Proteins; Disease Models, Animal; Gene Expression Regulation; Disease Models; Cytokines; Epidermis; Research Article; Signal Transduction

IL-17C is an epithelial cell-derived proinflammatory cytokine whose transcriptional regulation remains unclear. Analysis of the IL17C promoter region identified TCF4 as putative regulator, and siRNA knockdown in human keratinocytes (KCs) increased IL17C. stimulation KCs (along with IL-17A TNF-α stimulation) decreased NFKBIZ ZC3H12A expression IL-17RA/RE-dependent manner, thus creating a feedback loop. (MCPIP1/Regnase-1), immune-response also following knockdown, NFKBIZ, IL1B, IL36G, CCL20, CXCL1, revealing role for ZC3H12A. Examination lesional skin from KC-Tie2 inflammatory dermatitis mouse model decreases protein concomitant increases Zc3h12a that reversed genetic elimination Il17c, Il17ra, Il17re improvement phenotype. Conversely, interference Tcf4 Il17c exacerbated Together, these findings identify negative IL-17C, which, alone IL-17A, feed back to decrease manner. This loop further amplified by IL-17C-TCF4 autocrine promote self-sustaining inflammation.