Role of TNF receptor p55 in reactive arthritis induced by enteric bacteria

DI GENARO M. S.

Mendoza

Congreso; XXVI Reunión Científica Anual de la Sociedad de Biología de Cuyo; 2008

Sociedad de Biología de Cuyo

Reactive arthritis (ReA) is an aseptic synovitis that arises after certain types of gastrointestinal or genitourinary infections. The classical ReA-associated bacteria in the gastrointestinal tract include Yersinia, Salmonella, Shigella and Campylobacter. Since the pathogenesis of ReA is incompletely understood, appropriate treatments are not available. Abnormality of tumor necrosis factor (TNF)-a level has been detected in patients with ReA. TNF-a  mediates pleiotropic activities via two surface receptors, TNFRp55 (TNFRI) and TNFRp75 (TNFRII). TNFRp55 has been implicated in the majority of known TNF-a effects. We investigated the role of TNFRp55 in ReA induction after oral infection with Yersinia in TNFRp55-/- mice. Thus, wild-type and TNFRp55-/- C57BL/6 mice were orogastrically infected with Y. enterocolitica O:3, and monitored for survival and arthritis development. The bacterial load was determined in mesenteric lymph nodes (MLN), the spleen and joints. Interferon (IFN)-g, TNF-a and interleukin (IL)-10 mRNA expressions in MLN and joints were analyzed by RT-PCR. Articular pro-inflammatory cytokines such as IL-6, IL-1b, TNF-a, IFN-g and IL-17 were analysed by ELISA. Moreover, articular antibody responses to the most abundant articular collagens (type I and II), and Yersinia-specific antibodies were studied. Acute arthritis was evaluated after joint injection of Yersinia antigens. The survival rate was 60 % in TNFRp55-/- mice and 100 % in wild-type mice. TNFRp55-/- mice showed impaired bacterial clearance in MLN, the spleen and joints, and significantly higher IFN-g and TNF-a mRNA expressions in MLN. Clinical and histological examinations revealed that TNFRp55-/- mice developed severe and progressive arthritis. Furthermore, significantly higher articular pro-inflammatory cytokine levels were detected in TNFRp55-/- mice. Moreover, augmented articular type I and II collagen-, and outer membrane protein (OMP)-specific antibodies were detected in TNFRp55-/- mice. In addition, synovial inflammatory response was observed by joint OMP injection. In addition, we found that in vitro cultured TNFRp55-/- macrophages secreted higher pro-inflammatory mediators such as nitric oxide and IL-6 after heat killed Yersinia (HKY) or lipopolysaccharide (LPS) stimulation, compared with wild-type macrophages. Since TNFRp55 deficiency induced higher Yersinia susceptibility, ReA development, and articular pro-inflammatory responses, we concluded that TNFRp55-mediated immune mechanisms play a critical role preventing ReA after oral infection with Yersinia. Bacterial products such as OMP, particularly LPS, could contribute to ReA by induction of inflammatory response in TNFRp55-/- macrophages. The TNFRp55-/- mice is an appropriate animal model to study the cellular and molecular events of ReA, and it could be used to elucidate potential targets for a specific treatment for this disease.