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

Abstract

Reactive arthritis (ReA) is a type of arthritis originating from certain gastrointestinal or genitourinary infections. In previous studies, we reported the development of progressive Yersinia enterocolitica-induced ReA in mice lacking TNFR p55; however, the mechanisms underlying this effect are still uncertain. In this study, we investigated the impact of TNFR p55 deficiency in modulating Ag-specific Th1 and Th17 responses during this arthritogenic process. We found more severe ReA in TNFRp55−/− mice compared with their wild-type (WT) counterparts. This effect was accompanied by increased levels of Yersinia LPS in the joints of knockout mice. Analysis of the local cytokine profile revealed greater amounts of IFN-γ and IL-17 in arthritic joints of TNFRp55−/− mice compared with WT mice at day 21 postinfection. Moreover, altered IL-17 and IFN-γ production was observed in mesenteric and inguinal lymph nodes of Yersinia-infected TNFRp55−/− mice, as well as in spleen cells obtained from infected mice and restimulated ex vivo with bacterial Ags. Increased levels of cytokine secretion were associated with a greater frequency of CD4+IL-17+, CD4+IFN-γ+, and IL-17+IFN-γ+ cells in TNFRp55−/− mice compared with WT mice. Remarkably, Ab-mediated blockade of IL-17 and/or IFN-γ resulted in reduced joint histological scores in TNFRp55−/− mice. A mechanistic analysis revealed the involvement of p40, a common subunit of heterodimeric IL-12 and IL-23, in the generation of augmented IFN-γ and IL-17 production under TNFR p55 deficiency. Taken together, these data indicate that, in the absence of TNFR p55 signaling, Th1 and Th17 effector cells may act in concert to sustain the inflammatory response in bacterial-induced arthritogenic processes.

TNFRp55 modulates IL-6 and nitric oxide responses following Yersinia lipopolysaccharide stimulation in peritoneal macrophages

“…Furthermore, higher concentrations of IL-6 were detected in the joints of these mice which showed a severe chronic synovitis (Eliç abe et al 2010). These results are also consistent with those obtained in other arthritis models (Iwanami et al 2008).…”

Peripheral Neuroimmunoendocrine Interactions: Contribution of TNFRp55 to the Circadian Synchronization of Progesterone and Cytokine Production in Joints of Mice in Late Pregnancy

“…The role of IL-17 in the pathogenesis of synovitis in RA has been well documented [53]. Additionally, we have previously demonstrated that IL-17 mediates articular inflammation in reactive arthritis [34]. In the present study, we found that the articular IL-17 circadian rhythm was abolished in the KO mice, suggesting a role for TNF in the circadian regulation of IL-17.…”

“…Homogenates of ankle joints were obtained as previously described by Eliçabe et al [34]. Mouse IL-17, TNF, IL-6, and IL-10 were quantified in clarified joint homogenates by using capture enzyme-linked immunosorbent assay kits (eBioscience, San Diego, CA, USA) following the manufacturer’s instructions.…”

Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway

“…Our reported findings in mice showed that the increase in Th17 cells observed after anti-TNFα therapy was partly due to increased production of p40 1 2. This was based on observations that TNFα inhibits p40 production in vitro and that blockade of p40 inhibits the expansion of Th17 cells in vivo.…”

“…However, we made the unexpected discovery that in collagen-induced arthritis (CIA), treatment with anti-TNFα leads to an increase in pathogenic Th1 and Th17 cells 1. Mechanistically, the increase in Th1 and Th17 cells in TNFR1−/− mice may be attributable in part to increased production of p40, the common subunit of interleukin (IL)-12 and IL-23, cytokines that are important for the differentiation/survival of Th1 and Th17 cells, respectively 1 2…”