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Myositis Differentiation Exacerbates Virus-Induced Dependent Macrophage

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Myositis Differentiation Exacerbates Virus-Induced Dependent Macrophage SHP-1−Dependent Macrophage Differentiation Exacerbates Virus-Induced Myositis This information is current as Neva B. Watson, Karin M. Schneider and Paul T. Massa of September 26, 2021. J Immunol 2015; 194:2796-2809; Prepublished online 13 February 2015; doi: 10.4049/jimmunol.1402210 http://www.jimmunol.org/content/194/6/2796 Downloaded from References This article cites 88 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/194/6/2796.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology SHP-1–Dependent Macrophage Differentiation Exacerbates Virus-Induced Myositis Neva B. Watson,* Karin M. Schneider,* and Paul T. Massa*,† Virus-induced myositis is an emerging global affliction that remains poorly characterized with few treatment options. Moreover, muscle-tropic viruses often spread to the CNS, causing dramatically increased morbidity. Therefore, there is an urgent need to explore genetic factors involved in this class of human disease. This report investigates critical innate immune pathways affecting murine virus–induced myositis. Of particular importance, the key immune regulator src homology region 2 domain–containing phosphatase 1 (SHP-1), which normally suppresses macrophage-mediated inflammation, is a major factor in promoting clinical disease in muscle. We show that Theiler’s murine encephalomyelitis virus (TMEV) infection of skeletal myofibers induces inflammation and subsequent dystrophic calcification, with loss of ambulation in wild-type (WT) mice. Surprisingly, although 2/2 similar extensive myofiber infection and inflammation are observed in SHP-1 mice, these mice neither accumulate dead Downloaded from calcified myofibers nor lose ambulation. Macrophages were the predominant effector cells infiltrating WT and SHP-12/2 muscle, and an increased infiltration of immature monocytes/macrophages correlated with an absence of clinical disease in SHP-12/2 mice, whereas mature M1-like macrophages corresponded with increased myofiber degeneration in WT mice. Furthermore, blocking SHP-1 activation in WT macrophages blocked virus-induced myofiber degeneration, and pharmacologic ablation of macrophages inhibited muscle calcification in TMEV-infected WT animals. These data suggest that, following TMEV infection of muscle, SHP-1 promotes M1 differentiation of infiltrating macrophages, and these inflammatory macrophages are likely involved http://www.jimmunol.org/ in damaging muscle fibers. These findings reveal a pathological role for SHP-1 in promoting inflammatory macrophage differ- entiation and myofiber damage in virus-infected skeletal muscle, thus identifying SHP-1 and M1 macrophages as essential mediators of virus-induced myopathy. The Journal of Immunology, 2015, 194: 2796–2809. revalent human ssRNA viruses, including retroviruses, were described as targets for initial replication in the periphery flaviviruses, alphaviruses, picornaviruses, and rhabdovi- (22–29). Moreover, recent studies suggested that disease severity P ruses, are commonly associated with skeletal muscle in- of Chikungunya virus strains can be predicted by the ability of fection and inflammation resulting from either direct infection of each strain to infect myofibers (30, 31). Therefore, it is common myofibers or infiltrating inflammatory macrophages (1–15). As that muscle serves as an initial target for neurotropic viruses. by guest on September 26, 2021 a consequence of these infections, spreading of the virus from Another important aspect of these virus-induced neuromuscular muscle to CNS by retrograde axonal transport or viremia may diseases is the particular targeting of children. Many childhood occur, causing severe neuropathological complications (16–20). viral infections trigger CNS disease and/or muscle dysfunction, Therefore, skeletal muscle is a clinically significant target of virus with severe cases of muscle involvement manifesting in severe infections in humans, and the mechanisms involved in this process inflammatory myositis and/or rhabdomyolysis (32–35). Thus, virus must be elucidated further. infections involving skeletal muscle with common subsequent Among the most clinically relevant muscle-tropic viruses, neurologic involvement are an escalating clinical problem with arthropod-borne RNA viruses (arboviruses), including flaviviruses increased predilection for children. Therefore, defined animal and alphaviruses, are emerging disease threats worldwide in both models for these infections are needed to study genetic and im- developing and developed nations, and these infections are asso- mune mechanisms at play in the development of severe virus- ciated with a high incidence of neurologic manifestations (21). induced muscle and subsequent CNS disease. Alphaviruses, such as Ross River virus, Chikungunya virus, and Theiler’s murine encephalomyelitis virus (TMEV) is a neuro- Sindbis virus, were demonstrated to trigger debilitating muscle tropic picornavirus belonging to the cardiovirus genus that is and CNS disease in humans and mice, and skeletal muscle fibers made up of two subgroups (36). GDVII, the highly virulent strain, causes an acute paralytic disease with infection of neurons in the brain and spinal cord leading to encephalitis and death. Addi- *Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210; and †Department of Neurology, tionally, GDVII was reported to induce myositis marked by ex- State University of New York Upstate Medical University, Syracuse, NY 13210 tensive myofiber necrosis following i.m. inoculation (36–38). In Received for publication August 29, 2014. Accepted for publication January 8, 2015. contrast, attenuated strains of TMEV, including BeAn and DA, are This work was supported by National Institutes of Health Grant R01 NS072051. only neurotropic when inoculated intracranially into susceptible Address correspondence and reprint requests to Dr. Paul T. Massa, State University of strains of adult mice (36). These attenuated strains of TMEV are New York Upstate Medical University, 750 East Adams Street, WH 2237B, Syracuse, commonly used as a virus-induced model of multiple sclerosis, NY 13210. E-mail address: [email protected] often causing subclinical neuronal infection followed by persis- Abbreviations used in this article: BL/6, C57BL/6J; C3H, C3HeB/FeJLe; me/me, motheaten; mev/mev, viable motheaten; MFI, mean fluorescence intensity; P.I., post- tence in glia and inflammatory demyelination weeks to months infection; SAPE, streptavidin-PE; SHP-1, src homology region 2 domain–containing postinfection (P.I.) (36). Importantly, attenuated TMEV strains phosphatase 1; TMEV, Theiler’s murine encephalomyelitis virus; WT, wild-type. were demonstrated to induce a severe acute myositis following Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 i.m. inoculation and to induce an immune cell–mediated acute www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402210 The Journal of Immunology 2797 myositis following i.p. inoculation into several strains of suckling No. CCL-10). Plaque assays were performed to determine viral titer as PFU/ mice (38, 39). These studies indicate that TMEV infection of ml. Twelve-day-old me/me mice and normal littermates were inoculated i.p. 3 6 suckling mice may provide a model system for studying the with 100 ml containing 6 10 PFU BeAn TMEV. Mice were monitored daily for signs of skeletal muscle disease (hunched, abnormal gait, swollen pathogenesis of virus-induced muscle disease that may be relevant shoulders/hips). WT mice (n = 16) were sacrificed upon clinical signs of for increased childhood susceptibility to these viruses. muscle disease (9–15 d P.I.) unless otherwise noted, and development of We previously established that suckling Src homology region 2 skeletal muscle disease was verified by the presence of white calcified domain–containing phosphatase 1 (SHP-1)–deficient mice (moth- areas within skeletal muscle upon dissection. Alternatively, WT and me/me littermates were sacrificed at 5 d P.I. and processed for RNA, histological, eaten [me/me]) suffer CNS disease following intracranial or pe- and flow cytometry analysis. ripheral infection with the attenuated BeAn strain of TMEV, Twelve- to fourteen-day-old mev/mev mice and normal littermates were whereas wild-type (WT) mice are resistant to this disease (40– inoculated i.p. with 100 ml containing 6 3 105 to 3 3 106 PFU TMEV. Infections were independently repeated five times: once with 3 mev/mev 42). In this model, macrophages were found to mediate TMEV- v v induced demyelination in SHP-12/2 mice, because blocking and 3 WT animals; once with 1 me /me and 2
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