Splenic Ly6Chi monocytes are critical players in dystrophic muscle injury and repair

Rizzo, Giuseppe; Maggio, Rosanna Di; Benedetti, A.; Morroni, Jacopo; Bouché, Marina; Lozanoska-Ochser, Biliana

doi:10.1172/jci.insight.130807

Cited by 41 publications

(41 citation statements)

References 23 publications

(60 reference statements)

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“…Splenectomized mdx and mdx:CCR2 DM mice do not show improvements in muscle strength at 14 weeks or 6 months [41,42]. On the other hand, in our study, the running performance of the mdx:Smpd3 DM mice at 16 and even 60 weeks in the treadmill exhaustion test was better than that of the mdx mice.…”

Section: Discussioncontrasting

confidence: 72%

“…However, the origins of the Ly6C high and Ly6C low monocytes/macrophages in dystrophic muscles are unclear. Although bone marrow has been thought to be the principal source of monocytes, it was recently reported that splenic Ly6C high monocytes, which are outsourced from the bone marrow, contribute to recruitment and infiltration in dystrophic limb muscles, and to muscle fiber necrosis, during the early stages of the disease [42]. A reduction in infiltrated CD45 + cells in mdx mice improved muscle fiber necrosis and increased eMHC-positive regenerating fibers under a lack of splenic monocytes induced by splenectomy during the early phases of the condition.…”

Section: Discussionmentioning

confidence: 99%

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The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice

Matsuzaka

Tanihata

Ooshima

et al. 2020

BMC Med

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Background Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder and cognitive dysfunction caused by mutations in the dystrophin gene. It is characterized by excess inflammatory responses in the muscle and repeated degeneration and regeneration cycles. Neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3 (nSMase2/Smpd3) hydrolyzes sphingomyelin in lipid rafts. This protein thus modulates inflammatory responses, cell survival or apoptosis pathways, and the secretion of extracellular vesicles in a Ca2+-dependent manner. However, its roles in dystrophic pathology have not yet been clarified. Methods To investigate the effects of the loss of nSMase2/Smpd3 on dystrophic muscles and its role in the abnormal behavior observed in DMD patients, we generated mdx mice lacking the nSMase2/Smpd3 gene (mdx:Smpd3 double knockout [DKO] mice). Results Young mdx:Smpd3 DKO mice exhibited reduced muscular degeneration and decreased inflammation responses, but later on they showed exacerbated muscular necrosis. In addition, the abnormal stress response displayed by mdx mice was improved in the mdx:Smpd3 DKO mice, with the recovery of brain-derived neurotrophic factor (Bdnf) expression in the hippocampus. Conclusions nSMase2/Smpd3-modulated lipid raft integrity is a potential therapeutic target for DMD.

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Section: Discussioncontrasting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice

Matsuzaka

Tanihata

Ooshima

et al. 2020

BMC Med

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“…In agreement with established splenic changes in dystrophic animal models of Duchenne muscular dystrophy, such as morphological adaptations in the white pulp domain of the spleen ( Santos et al., 2013 ) and altered levels of immune cells in the spleen and enhanced migration of inflammatory cells from the splenic reservoir to dystrophic muscle tissues ( Farini et al., 2016 ; Giordano et al., 2015 ; Mojumdar et al., 2014 , 2016 ; Ouisse et al., 2019 ), this investigation has established considerable effects on the spleen proteome owing to deficiency in the full-length dystrophin isoform Dp427-M. Since the spleen acts as a dominant reservoir for inflammatory cells ( Ingersoll et al., 2011 ) and splenic monocytes were recently shown to play an important role during chronic inflammation of dystrophic fibers ( Rizzo et al., 2020 ), the novel proteomic findings are in agreement with the pathophysiological idea of a connection between the lymphoid system and dystrophic muscles with an inflammatory phenotype ( Villalta et al., 2015 ; Tidball et al., 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…The main functions of the spleen include the removal of abnormal erythrocytes, antigen detection, and antibody production ( Lewis et al., 2019 ). In dystrophic organisms with an almost complete loss of the full-length Dp427-M isoform of dystrophin, abnormalities in the spleen were previously reported to include morphological adaptations in relation to lymph nodes in the white pulp region of the mdx mouse spleen ( Santos et al., 2013 ), as well as altered levels of splenic inflammatory monocytes and increased migration of immune cells from the splenic reservoir to injured dystrophic fibers ( Farini et al., 2016 ; Giordano et al., 2015 ; Mojumdar et al., 2014 , 2016 ; Ouisse et al., 2019 ; Rizzo et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…The proteomic findings suggest that a variety of metabolic and cellular processes are affected in the mdx-4cv spleen, which confirms the usefulness of this genetic mouse model for studying the complex pathology of Duchenne muscular dystrophy. A pathophysiological connection appears to exist between skeletal muscle wasting, which is characterized by progressive fiber degeneration and inflammation ( Allen et al., 2016 ; Tidball et al., 2018 ), and alterations in the lymphoid system due to primary abnormalities in the dystrophin gene ( Rizzo et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Proteome-wide Changes in the mdx-4cv Spleen due to Pathophysiological Cross Talk with Dystrophin-Deficient Skeletal Muscle

et al. 2020

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Summary Duchenne muscular dystrophy is primarily characterized by progressive muscle wasting due to deficiency in the membrane cytoskeletal protein dystrophin but is also associated with body-wide cellular disturbances in a variety of non-muscle tissues. In this study, we have focused on the comparative proteomic analysis of the spleen and established considerable changes in this crucial secondary lymphoid organ from the genetic mdx-4cv mouse model of dystrophinopathy. An apparent short isoform of dystrophin and associated glycoproteins were identified in spleen by mass spectrometry but appear not be affected in muscular dystrophy. In contrast, the mdx-4cv spleen showed significant proteome-wide changes in other protein species that are involved in metabolism, signaling, and cellular architecture. Since the spleen plays a key role in the immune response, these proteomic alterations may reflect pathophysiological cross talk between the lymphoid system and dystrophic muscles, which are affected by both fiber degeneration and inflammation.

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Central and peripheral myeloid-derived suppressor cell-like cells are closely related to the clinical severity of multiple sclerosis

et al. 2023

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Multiple sclerosis (MS) is a highly heterogeneous demyelinating disease of the central nervous system (CNS) that needs for reliable biomarkers to foresee disease severity. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population with an important role in MS. The monocytic-MDSCs (M-MDSCs) share the phenotype with Ly-6Chi-cells in the MS animal model, experimental autoimmune encephalomyelitis (EAE), and have been retrospectively related to the severity of the clinical course in the EAE. However, no data are available about the presence of M-MDSCs in the CNS of MS patients or its relation with the future disease aggressiveness. In this work, we show for the first time cells exhibiting all the bona-fide phenotypical markers of M-MDSCs associated with MS lesions, whose abundance in these areas appears to be directly correlated with longer disease duration in primary progressive MS patients. Moreover, we show that blood immunosuppressive Ly-6Chi-cells are strongly related to the future severity of EAE disease course. We found that a higher abundance of Ly-6Chi-cells at the onset of the EAE clinical course is associated with a milder disease course and less tissue damage. In parallel, we determined that the abundance of M-MDSCs in blood samples from untreated MS patients at their first relapse is inversely correlated with the Expanded Disability Status Scale (EDSS) at baseline and after a 1-year follow-up. In summary, our data point to M-MDSC load as a factor to be considered for future studies focused on the prediction of disease severity in EAE and MS.

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Splenic Ly6Chi monocytes are critical players in dystrophic muscle injury and repair

Cited by 41 publications

References 23 publications

The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice

The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice

Proteome-wide Changes in the mdx-4cv Spleen due to Pathophysiological Cross Talk with Dystrophin-Deficient Skeletal Muscle

Central and peripheral myeloid-derived suppressor cell-like cells are closely related to the clinical severity of multiple sclerosis

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