title: The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response.
abstract: Connective tissue growth factor (CTGF/CCN2) is a matricellular protein susceptible to proteolytic degradation. CCN2 levels have been suggested as a potential risk biomarker in several chronic diseases. In body fluids, CCN2 full-length and its degradation fragments can be found; however, their in vivo effects are far from being elucidated. CCN2 was described as a profibrotic mediator, but this concept is changing to a proinflammatory cytokine. In vitro, CCN2 full-length and its C-terminal module IV (CCN2(IV)) exert proinflammatory properties. Emerging evidence suggest that Th17 cells, and its effector cytokine IL-17A, participate in chronic inflammatory diseases. Our aim was to explore whether CCN2(IV) could regulate the Th17 response. In vitro, stimulation of human naive CD4+ T lymphocytes with CCN2(IV) resulted in differentiation to Th17 phenotype. The in vivo effects of CCN2(IV) were studied in C57BL/6 mice. Intraperitoneal administration of recombinant CCN2(IV) did not change serum IL-17A levels, but caused an activation of the Th17 response in the kidney, characterized by interstitial infiltration of Th17 (IL17A+/CD4+) cells and upregulation of proinflammatory mediators. In CCN2(IV)-injected mice, elevated renal levels of Th17-related factors (IL-17A, IL-6, STAT3 and RORγt) were found, whereas Th1/Th2 cytokines or Treg-related factors (TGF-β and Foxp-3) were not modified. Treatment with an anti-IL-17A neutralizing antibody diminished CCN2(IV)-induced renal inflammation. Our findings unveil that the C-terminal module of CCN2 induces the Th17 differentiation of human Th17 cells and causes a renal Th17 inflammatory response. Furthermore, these data bear out that IL-17A targeting is a promising tool for chronic inflammatory diseases, including renal pathologies.
authors: Cellular Biology in Renal Diseases Laboratory, Instituto de Investigacion Sanitaria Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors: Raquel
authors: R
authors: Rodrigues-Díez
authors: Raúl R
authors: RR
authors: Rodrigues-Díez
authors: Sandra
authors: S
authors: Rayego-Mateos
authors: Beatriz
authors: B
authors: Suarez-Alvarez
authors: Carolina
authors: C
authors: Lavoz
authors: Luiz
authors: L
authors: Stark Aroeira
authors: Elsa
authors: E
authors: Sánchez-López
authors: Macarena
authors: M
authors: Orejudo
authors: Matilde
authors: M
authors: Alique
authors: Carlos
authors: C
authors: Lopez-Larrea
authors: Alberto
authors: A
authors: Ortiz
authors: Jesús
authors: J
authors: Egido
authors: Marta
authors: M
authors: Ruiz-Ortega
mesh_terms: D000818:Animals; D055513:Connective Tissue Growth Factor / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000097:blood*; D007668:Kidney / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058504:Th17 Cells / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D020381:Interleukin-17; D014157:Transcription Factors; D055513:Connective Tissue Growth Factor