The immunoproteasomes are key to regulate myokines and MHC class I expression in idiopathic inflammatory myopathies

Bhattarai, Salyan; Ghannam, Khetam; Krause, Sabine; Benveniste, Olivier; Marg, Andreas; Bruin, Gerjan de; Xin, Bo‐Tao; Overkleeft, Hermen S.; Spuler, Simone; Stenzel, Werner; Feist, Eugen

doi:10.1016/j.jaut.2016.08.004

Cited by 37 publications

(48 citation statements)

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“…We failed to induce C 2 C 12 cells upregulate MHC class I or class II using LPS or TNF‐α as the stimulators (data not shown). We found IFN‐γ is the best candidate for triggering immunological phenotypes of muscle cells in vitro, which is in agreement with the other reports (Goebels et al, ; Michaelis et al, ; Wiendl et al, ; Bhattarai et al, ). We have now verified that MHC‐I (H‐2K b ) can be constitutively expressed by C 2 C 12 myoblasts and myotubes, and the level increased after treating by IFN‐γ.…”

Section: Discussionsupporting

confidence: 93%

Immunological Behavior Analysis of Muscle Cells under IFN‐γ Stimulation in Vitro and in Vivo

Ding

Huang

Zhu

et al. 2018

The Anatomical Record

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Muscle cells could serve as antigen-presenting cells, and participate in the activation of immune response. Immunological characteristics of muscle cells, and their capacities to equip themselves with immunorelevant molecules, remain to be elucidated. In this study, we investigated the immunological properties of myoblasts and differentiated myotubes in vitro and in vivo, under the IFN-γ induced inflammatory condition. We found that the fused C C myotubes are more sensitive to inflammatory stimulation, and significantly upregulated the expression levels of MHC-I/II and TLR3/7 molecules, than that of proliferated myoblasts. As well, some co-stimulatory/-inhibitory molecules, including CD40, CD86, ICAM-I, ICOS-L, and PD-L1, were prominently upregulated in IFN-γ induced myotubes. Notably, we detected the protein levels of ASC, NLRP3, and Caspase-1 increased in stimulated myotubes, and IL-1β in cell culture supernatant, implying the activation of NLRP3 inflammasomes in IFN-γ treated myotubes. The pro-inflammatory cytokines and chemokines mRNA levels in IFN-γ induced C C myotubes and myoblasts, involving IL-1, IL-6, and MCP-1, increased markedly. T cell activation test further verified IFN-γ induced C C myotubes prompt to the proliferation of the splenic CD4 and CD8 T cells. In Cardiotoxin-damaged tibialis anterior (TA) muscle, some regenerated myofibers expressed both MHC class I and class II molecules under IFN-γ enhanced inflammatory condition. Thus, our work demonstrates that muscle cells are active participants of local immune reactions. Anat Rec, 301:1551-1563, 2018. © 2018 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 93%

Immunological Behavior Analysis of Muscle Cells under IFN‐γ Stimulation in Vitro and in Vivo

Ding

Huang

Zhu

et al. 2018

The Anatomical Record

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“…BAG3 mutations may also lead to severe myofibrillar myopathy (41), cardiomyopathy (35) and neuropathy (36), highlighting the relevance of this molecule in the neuromuscular system. Moreover, we have recently highlighted that the lysosomeindependent immune proteasome machinery is involved in the degradation of antigen peptides presented at the cellular surface via MHC class I in IMNM (12). Finally, ER stress and the unfolded protein response (UPR), pathways that deal with the processing of proteins transported to the ER, comprising a multitude of different regulating chaperones, may also be altered in certain forms of myositis.…”

Section: Introductionmentioning

confidence: 99%

Sequestosome‐1 (p62) expression reveals chaperone‐assisted selective autophagy in immune‐mediated necrotizing myopathies

et al. 2019

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Diffuse myofiber necrosis in the context of inflammatory myopathy is the hallmark of immune‐mediated necrotizing myopathy (IMNM). We have previously shown that skeletal muscle fibers of IMNM patients may display nonrimmed vacuoles and sarcoplasmic irregularities. The dysfunctional chaperone activity has been linked to the defective assembly of skeletal muscle proteins and their degradation via lysosomes, autophagy and the proteasomal machinery. This study was undertaken to highlight a chaperone‐assisted selective autophagy (CASA) pathway, functionally involved in protein homeostasis, cell stress and the immune response in skeletal muscle of IMNM patients. Skeletal muscle biopsies from 54 IMNM patients were analyzed by immunostaining, as well as by qPCR. Eight biopsies of sIBM patients served as pathological controls, and eight biopsies of nondisease control subjects were included. Alteration of autophagy was detectable in all IMNM biopsy samples highlighted via a diffuse sarcoplasmic staining pattern by p62 and LC3 independent of vacuoles. This pattern was at variance with the coarse focal staining pattern mostly confined to rimmed vacuoles in sIBM. Colocalization of p62 with the chaperone proteins HSP70 and αB‐crystalline points to the specific targeting of misfolded proteins to the CASA machinery. Bcl2‐associated athanogene 3 (BAG3) positivity of these fibers emphasizes the selectivity of autophagy processes and these fibers also express MHC class I sarcolemma. Expression of genes involved in autophagy and endoplasmic reticulum (ER) stress pathways studied here is significantly upregulated in IMNM. We highlight that vacuoles without sarcolemmal features may arise in IMNM muscle biopsies, and they must not be confounded with sIBM‐specific vacuoles. Further, we show the activation of selective autophagy and emphasize the role of chaperones in this context. CASA occurs in IMNM muscle, and specific molecular pathways of autophagy differ from the ones in sIBM, with p62 as a unique identifier of this process.

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“…In addition, serum levels of these cytokines are elevated in patients with NNS, as well as in patients with CANDLE syndrome [1,16] Intriguingly, plasma IP-10 level is elevated in over 90% of patients with major idiopathic inflammatory myopathies, suggesting a common immunoserological feature between this type of myopathies and NNS/PRAAS [5]. Immunoproteasome subunits b1i and b5i have been reported to regulate the expression of MHC-I in idiopathic inflammatory myositis [17]. In NNS cases, impairment of immunoproteasome function due to subunit b5i mutation could lead to increased expression of MHC-I as a result of a compensatory mechanism.…”

Section: Discussionmentioning

confidence: 99%

Myositis with sarcoplasmic inclusions in Nakajo–Nishimura syndrome: a genetic inflammatory myopathy

Ayaki

Murata

Kanazawa

et al. 2020

Neuropathology Appl Neurobio

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(2020) Neuropathology and Applied Neurobiology 46, 579-587 Myositis with sarcoplasmic inclusions in Nakajo-Nishimura syndrome: a genetic inflammatory myopathy Aims: Nakajo-Nishimura syndrome (NNS) is an autosomal recessive disease caused by biallelic mutations in the PSMB8 gene that encodes the immunoproteasome subunit b5i. There have been only a limited number of reports on the clinicopathological features of the disease in genetically confirmed cases. Methods: We studied clinical and pathological features of three NNS patients who all carry the homozygous p.G201V mutations in PSMB8. Patients' muscle specimens were analysed with histology and immunohistochemistry. Results: All patients had episodes of typical periodic fever and skin rash, and later developed progressive muscle weakness and atrophy, similar to previous reports. Oral corticosteroid was used for treatment but showed no obvious efficacy. On muscle pathology, lymphocytes were present in the endomysium surrounding non-necrotic fibres, as well as in the perimysium perivascular area. Nearly all fibres strongly expressed MHC-I in the sarcolemma. In the eldest patient, there were abnormal protein aggregates in the sarcoplasm, immunoreactive to p62, TDP-43 and ubiquitin antibodies. Conclusions: These results suggest that inflammation, inclusion pathology and aggregation of abnormal proteins underlie the progressive clinical course of the NNS pathomechanism.

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The immunoproteasomes are key to regulate myokines and MHC class I expression in idiopathic inflammatory myopathies

Cited by 37 publications

References 50 publications

Immunological Behavior Analysis of Muscle Cells under IFN‐γ Stimulation in Vitro and in Vivo

Immunological Behavior Analysis of Muscle Cells under IFN‐γ Stimulation in Vitro and in Vivo

Sequestosome‐1 (p62) expression reveals chaperone‐assisted selective autophagy in immune‐mediated necrotizing myopathies

Myositis with sarcoplasmic inclusions in Nakajo–Nishimura syndrome: a genetic inflammatory myopathy

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