Lack of TNFR p55 Results in Heightened Expression of IFN- and IL-17 during the Development of Reactive Arthritis

RICARDO J. ELIÇABE, ETHELINA CARGNELUTTI, MARÍA I. SERER,PATRICIA W. STEGE, SUSANA R. VALDEZ, MARTA A. TOSCANO,GABRIEL A. RABINOVICH AND MARÍA S. DI GENARO

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Lugar: United States; Año: 2010 vol. 185 p. 4485 - 4495

0022-1767

Reactive arthritis (ReA) is a type of arthritis originating from certain gastrointestinal or genitourinary infections. In previousstudies, we reported the development of progressive Yersinia enterocolitica-induced ReA in mice lacking TNFR p55; however, themechanisms underlying this effect are still uncertain. In this study, we investigated the impact of TNFR p55 deficiency in modulatingAg-specific Th1 and Th17 responses during this arthritogenic process. We found more severe ReA in TNFRp552/2 micecompared with their wild-type (WT) counterparts. This effect was accompanied by increased levels of Yersinia LPS in the joints ofknockout mice. Analysis of the local cytokine profile revealed greater amounts of IFN-g and IL-17 in arthritic joints of TNFRp552/2mice compared with WT mice at day 21 postinfection. Moreover, altered IL-17 and IFN-g production was observed in mesentericand inguinal lymph nodes of Yersinia-infected TNFRp552/2 mice, as well as in spleen cells obtained from infected mice andrestimulated ex vivo with bacterial Ags. Increased levels of cytokine secretion were associated with a greater frequency of CD4+IL-17+, CD4+IFN-g+, and IL-17+IFN-g+ cells in TNFRp552/2 mice compared with WT mice. Remarkably, Ab-mediated blockadeof IL-17 and/or IFN-g resulted in reduced joint histological scores in TNFRp552/2 mice. A mechanistic analysis revealed the involvementof p40, a common subunit of heterodimeric IL-12 and IL-23, in the generation of augmented IFN-g and IL-17 productionunder TNFR p55 deficiency. Taken together, these data indicate that, in the absence of TNFR p55 signaling, Th1 and Th17effector cells may act in concert to sustain the inflammatory response in bacterial-induced arthritogenic processes.