The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

• Published in: Laboratory investigation 2013-07, Vol.93 (7), p.812-824
• Main Authors: Rodrigues-Díez, Raquel, Rodrigues-Díez, Raúl R, Rayego-Mateos, Sandra, Suarez-Alvarez, Beatriz, Lavoz, Carolina, Stark Aroeira, Luiz, Sánchez-López, Elsa, Orejudo, Macarena, Alique, Matilde, Lopez-Larrea, Carlos, Ortiz, Alberto, Egido, Jesús, Ruiz-Ortega, Marta
• Format: Article
• Language: English
• Subjects: 631/250/1619/554/1898/1273; 631/250/2152/1566; 631/250/256; Animals; Connective Tissue Growth Factor - administration & dosage; Connective Tissue Growth Factor - metabolism; Humans; Interleukin-17 - blood; Kidney - immunology; Kidney - metabolism; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Pathology; research-article; Th17 Cells - physiology; Transcription Factors - metabolism; Up-Regulation
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2013.67

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 ROR γ t) 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.