Enhancement of antibody-induced arthritis via Toll-like receptor 2 stimulation is regulated by granulocyte reactive oxygen species.
ABSTRACT The suppressive role of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) complex-derived reactive oxygen species (ROS) in adaptive immunity-driven arthritis models is well established. In this study, we aimed to investigate the role of NOX2 complex-derived ROS in a model of innate immunity-driven arthritis and to identify the ROS-regulated innate receptors that control arthritis. We used collagen antibody-induced arthritis (CAIA), which is a T and B lymphocyte-independent model of the effector phase of arthritis and is induced by well-defined monoclonal arthritogenic antibodies and enhanced by injection of lipopolysaccharide (LPS). CAIA was induced in both wild-type and Ncf1 mutant mice that lack phagocyte oxidative burst, and stimulated with LPS and other agents to activate innate immune responses. We found that both LPS and lipomannan enhanced CAIA more potently in the presence of functional phagocyte ROS production than in its absence. The ROS-dependent enhancement of CAIA was regulated by TLR2, but not by TLR4 stimulation, and was driven by granulocytes, whereas macrophages did not contribute to the phenotype. In addition, we report that collagen-induced arthritis was not affected by the functionality of the TLR4. We report that TLR2 signaling as an important ROS-regulated proinflammatory pathway leads to severe neutrophil-dependent inflammation in murine CAIA and conclude that the TLR2 pathway is modulated by phagocyte ROS to stimulate the development of arthritis.
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ABSTRACT: Polymers as an adjuvant are capable of enhancing the vaccine potential against various infectious diseases and also are being used to study the actual autoimmune responses using self-antigen(s) without involving any major immune deviation. Several natural polysaccharides and their derivatives originating from microbes and plants have been tested for their adjuvant potential. Similarly, numerous synthetic polymers including polyelectrolytes, polyesters, polyanhydrides, non-ionic block copolymers and external stimuli responsive polymers have demonstrated adjuvant capacity using different antigens. Adjuvant potential of these polymers mainly depends on their solubility, molecular weight, degree of branching and the conformation of polymeric backbone. These polymers have the ability not only to activate humoral but also cellular immune responses in the host. The depot effect, which involves slow release of antigen over a long duration of time, using different forms (particulate, solution and gel) of polymers, and enhances the co-stimulatory signals for optimal immune activation, is the underlying principle of their adjuvant properties. Possibly, polymers may also interact and activate various toll-like receptors and inflammasomes, thus involving several innate immune system players in the ensuing immune response. Biocompatibility, biodegradability, easy production and purification, and non-toxic properties of most of the polymers make them attractive candidates for substituting conventional adjuvants that have undesirable effects in the host.Journal of The Royal Society Interface 02/2013; 10(79):20120536. · 4.91 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: Ischemic preconditioning (IPC) is gaining attention as a novel neuroprotective therapy and could provide an improved mechanistic understanding of tolerance to cerebral ischemia. The purpose of this article is to review the recent work in the field of IPC and its applications to clinical scenarios. RECENT FINDINGS: The cellular signaling pathways that are activated following IPC are now better understood and have enabled investigators to identify several IPC mimetics. Most of these studies were performed in rodents, and efficacy of these mimetics remains to be evaluated in human patients. Additionally, remote ischemic preconditioning (RIPC) may have higher translational value than IPC. Repeated cycles of temporary ischemia in a remote organ can activate protective pathways in the target organ, including the heart and brain. Clinical trials are underway to test the efficacy of RIPC in protecting brain against subarachnoid hemorrhage. SUMMARY: IPC, RIPC, and IPC mimetics have the potential to be therapeutic in various clinical scenarios. Further understanding of IPC-induced neuroprotection pathways and utilization of clinically relevant animal models are necessary to increase the translational potential of IPC in the near future.Current opinion in neurology 11/2012; · 5.43 Impact Factor
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ABSTRACT: Objective: Bone loss in arthritis is a complex process including bone erosions, periarticular and generalized bone loss. The antigen-induced arthritis (AIA) model is mainly used to study synovitis and joint destruction, including bone erosions, while periarticular bone loss is less investigated. The main aim of this study was to characterize and establish AIA as a model for periarticular bone loss. We also determined the importance of NADPH oxidase 2 (NOX2) derived reactive oxygen species (ROS) for periarticular bone loss. Methods: AIA was induced in one knee by a local antigen injection and the other knee was used as non-arthritic control. At termination the knees were collected for histology. Periarticular bone mineral density (BMD) was investigated using peripheral Quantitative Computed Tomography (pQCT). Flow cytometry analyses were performed on synovial and bone marrow cells. Results: AIA resulted in decreased periarticular trabecular BMD and increased frequencies of preosteoclasts, neutrophils and monocytes in the arthritic synovial tissue. Arthritis resulted in an elevated capability to produce ROS. However, AIA induction in Ncf1(*/*) mice, lacking NOX2 derived ROS, and control mice resulted in similar reduction in periarticular trabecular BMD. Conclusions: AIA resulted in periarticular bone loss associated with local effects on inflammatory cells and osteoclasts. Furthermore, using this model, we conclude that NOX2 derived ROS production is not essential for inflammation-mediated periarticular bone loss. Thus, AIA can be used as a model to investigate the pathogenesis of local inflammation-mediated bone loss. © 2013 American College of Rheumatology.Arthritis & Rheumatology 08/2013; · 7.48 Impact Factor