Neutralization of TNFR-1 and TNFR-2 modulates S. aureus induced septic arthritis by regulating the levels of pro inflammatory and anti inflammatory cytokines during the progression of the disease.

Abstract

Staphylococcal septic arthritis remains a serious medical concern due to rapid and sustained production of inflammatory cytokines that leads to progressive and irreversible joint destruction with high mortality rate in patients despite adequate antibiotics treatment. TNF-α signalling via TNFR-1 contributes to arthritic destruction by aggravating inflammation. Impact of TNFR-2 signalling is not well established in this aspect. Hence the objective of our study was to evaluate the role of dual neutralization TNFR-1 and TNFR-2 in the pathogenesis of S. aureus infection induced septic arthritis. Mice were infected with live S. aureus (5 × 106 cells/ml) followed by administration of TNFR-1and TNFR-2 neutralizing antibody. To measure arthritis index and osteoclastogenesis, histology result in joint tissue and TRAP staining images of arthritis joints have been performed respectively. Maximum reduction in the joint and paw swelling was observed in infected mice treated with both TNFR-1 and TNFR-2 antibody. NF-κB signalling was found to be mainly regulated by TNFR-1 whereas TNFR-2 significantly modulated JNK pathway. Lowest levels of inflammatory cytokines like TNF-α, IL-1β, IL-6, and IFN-γ were observed in both serum and synovial tissues signifying maximum protection in S. aureus arthritis during combination treatment. However IFN-γ and IL-10 levels were significantly altered by TNFR-2 neutralization that indicates both pro and anti inflammatory role of TNFR-2 respectively. Highest decrement in ROS concentration, iNOS expression with least MPO and lysozyme activity was detected in case of combined neutralization. During the early phase of infection all the aforesaid inflammatory parameters remained elevated due to lack of IL-10 as a result of TNFR-2 neutralization as IL-10 negatively modulates pro inflammatory cytokines. Increase in inflammatory cytokines during early phase might also be responsible for decreased bacterial count in TNFR-2 neutralized groups. Thus it can be suggested that combined administration of TNFR-1 and TNFR-2 antibody has a beneficial effect against the severity of S. aureus induced arthritis.

• Authors: Sahin Sultana, Biswadev Bishayi
• Journal: Immunology letters (Immunol Lett) Vol. 196 Pg. 33-51 (04 2018) ISSN: 1879-0542 [Electronic] Netherlands
• PMID: 29339199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antibodies, Neutralizing
• Cytokines
• Inflammation Mediators
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II

Topics

• Animals
• Antibodies, Neutralizing (immunology, pharmacology)
• Arthritis, Infectious (etiology, immunology, metabolism)
• Blotting, Western
• Cytokines (immunology, metabolism)
• Disease Progression
• Host-Pathogen Interactions (drug effects, immunology)
• Inflammation Mediators (immunology, metabolism)
• Joints (drug effects, immunology, microbiology)
• Male
• Mice
• Receptors, Tumor Necrosis Factor, Type I (antagonists & inhibitors, immunology)
• Receptors, Tumor Necrosis Factor, Type II (antagonists & inhibitors, immunology)
• Staphylococcal Infections (complications, immunology, microbiology)
• Staphylococcus aureus (drug effects, immunology, physiology)