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      Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfer mouse model of autoimmune arthritis

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          Highlights

          • Capsaicin-sensitive sensory nerves are protective against autoimmune arthritis.

          • Desensitization of these fibers increase immune cell activation and edema.

          • Sensory denervation enhances ROS production, MMP activity and arthritic changes.

          • Late mechanical hyperalgesia is decreased after destroying these sensory nerves.

          Abstract

          Objective

          The K/BxN serum-transfer arthritis is a widely-used translational mouse model of rheumatoid arthritis, in which the immunological components have thoroughly been investigated. In contrast, little is known about the role of sensory neural factors and the complexity of neuro–immune interactions. Therefore, we analyzed the involvement of capsaicin-sensitive peptidergic sensory nerves in autoantibody-induced arthritis with integrative methodology.

          Methods

          Arthritogenic K/BxN or control serum was injected to non-pretreated mice or resiniferatoxin (RTX)-pretreated animals where capsaicin-sensitive nerves were inactivated. Edema, touch sensitivity, noxious heat threshold, joint function, body weight and clinical arthritis severity scores were determined repeatedly throughout two weeks. Micro-CT and in vivo optical imaging to determine matrix-metalloproteinase (MMP) and neutrophil-derived myeloperoxidase (MPO) activities, semiquantitative histopathological scoring and radioimmunoassay to measure somatostatin in the joint homogenates were also performed.

          Results

          In RTX-pretreated mice, the autoantibody-induced joint swelling, arthritis severity score, MMP and MPO activities, as well as histopathological alterations were significantly greater compared to non-pretreated animals. Self-control quantification of the bone mass revealed decreased values in intact female mice, but significantly greater arthritis-induced pathological bone formation after RTX-pretreatment. In contrast, mechanical hyperalgesia from day 10 was smaller after inactivating capsaicin-sensitive afferents. Although thermal hyperalgesia did not develop, noxious heat threshold was significantly higher following RTX pretreatment. Somatostatin-like immunoreactivity elevated in the tibiotarsal joints in non-pretreated, which was significantly less in RTX-pretreated mice.

          Conclusions

          Although capsaicin-sensitive sensory nerves mediate mechanical hyperalgesia in the later phase of autoantibody-induced chronic arthritis, they play important anti-inflammatory roles at least partially through somatostatin release.

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          Most cited references54

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          Organ-specific disease provoked by systemic autoimmunity.

          Rheumatoid arthritis (RA) is a chronic joint disease characterized by leukocyte invasion and synoviocyte activation followed by cartilage and bone destruction. Its etiology and pathogenesis are poorly understood. We describe a spontaneous mouse model of this syndrome, generated fortuitously by crossing a T cell receptor (TCR) transgenic line with the NOD strain. All offspring develop a joint disease highly reminiscent of RA in man. The trigger for the murine disorder is chance recognition of a NOD-derived major histocompatibility complex (MHC) class II molecule by the transgenic TCR; progression to arthritis involves CD4+ T, B, and probably myeloid cells. Thus, a joint-specific disease need not arise from response to a joint-specific antigen but can be precipitated by a breakdown in general mechanisms of self-tolerance resulting in systemic self-reactivity. We suggest that human RA develops by an analogous mechanism.
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            Nociceptive Sensory Neurons Drive Interleukin-23 Mediated Psoriasiform Skin Inflammation

            The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbors specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17 producing γδ T cells (γδT17), whose aberrant activation by IL-23 can provoke psoriasis-like inflammation 1–4 . The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibers. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear 5,6 . Here, we have exposed the skin of mice to imiquimod (IMQ), which induces IL-23 dependent psoriasis-like inflammation 7,8 . We show that a subset of sensory neurons expressing the ion channels TRPV1 and NaV1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors 9–11 , DDCs failed to produce IL-23 in IMQ exposed skin. Consequently, the local production of IL-23 dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were dramatically reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response 12 . These findings indicate that TRPV1+NaV1.8+ nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.
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              From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins.

              Rheumatoid arthritis is a common and debilitating autoimmune disease whose cause and mechanism remain a mystery. We recently described a T cell receptor transgenic mouse model that spontaneously develops a disease with most of the clinical, histological, and immunological features of rheumatoid arthritis in humans. Disease development in K/BxN mice is initiated by systemic T cell self-reactivity; it requires T cells, as expected, but B cells are also needed, more surprisingly. Here, we have identified the role of B cells as the secretion of arthritogenic immunoglobulins. We suggest that a similar scenario may unfold in some other arthritis models and in human patients, beginning with pervasive T cell autoreactivity and ending in immunoglobulin-provoked joint destruction.
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                Author and article information

                Contributors
                Journal
                Brain Behav Immun
                Brain Behav. Immun
                Brain, Behavior, and Immunity
                Academic Press
                0889-1591
                1090-2139
                1 March 2015
                March 2015
                : 45
                : 50-59
                Affiliations
                [a ]Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Pécs, Hungary
                [b ]János Szentágothai Research Centre, Molecular Pharmacology Research Team, University of Pécs, Pécs, Hungary
                [c ]Centre for Neuroscience, University of Pécs, Medical School, Pécs, Hungary
                [d ]Department of Pathology, University of Pécs, Medical School, Pécs, Hungary
                [e ]Department of Physiology, and MTA-SE “Lendület” Inflammation Physiology Research Group, Semmelweis University, School of Medicine, Budapest, Hungary
                [f ]PharmInVivo Ltd, Pécs, Hungary
                [g ]MTA-PTE NAP B Pain Research Group, Hungary
                Author notes
                [* ]Corresponding author at: Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti u. 12., H-7624 Pécs, Hungary. Tel.: +36 72 536 000/35591; fax: +36 72 536 218. zsuzsanna.helyes@ 123456aok.pte.hu
                [1]

                These authors made equal contributions to this work.

                Article
                S0889-1591(14)00575-3
                10.1016/j.bbi.2014.12.012
                4349500
                25524130
                2ec090a1-4ba0-4a27-bd58-7984ec264f0c
                © 2014 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 September 2014
                : 18 November 2014
                : 9 December 2014
                Categories
                Article

                Neurosciences
                capsaicin-sensitive sensory nerves,pain,inflammation,somatostatin,matrix-metalloproteinase

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