{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T22:11:23Z","timestamp":1790028683318,"version":"4.0.1"},"reference-count":46,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CNRS"},{"name":"AFM T\u00e9l\u00e9thon"},{"name":"Fondation pour la Recherche M\u00e9dicale"},{"name":"Hospices Civils de Lyon"},{"name":"University Claude Bernard Lyon 1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Sarcoidosis is a multisystemic disease characterized by non-caseating granuloma infiltrating various organs. The form with symptomatic muscular involvement is called muscular sarcoidosis. The impact of immune cells composing the granuloma on the skeletal muscle is misunderstood. Here, we investigated the granuloma\u2013skeletal muscle interactions through spatial transcriptomics on two patients affected by muscular sarcoidosis. Five major transcriptomic clusters corresponding to perigranuloma, granuloma, and three successive muscle tissue areas (proximal, intermediate, and distal) around the granuloma were identified. Analyses revealed upregulated pathways in the granuloma corresponding to the activation of T-lymphocytes and monocytes\/macrophages cytokines, the upregulation of extracellular matrix signatures, and the induction of the TGF-\u03b2 signaling in the perigranuloma. A comparison between the proximal and distal muscles to the granuloma revealed an inverse correlation between the distance to the granuloma and the upregulation of cellular response to interferon-\u03b3\/\u03b1, TNF-\u03b1, IL-1,4,6, fibroblast proliferation, epithelial to mesenchymal cell transition, and the downregulation of muscle gene expression. These data shed light on the intercommunications between granulomas and the muscle tissue and provide pathophysiological mechanisms by showing that granuloma immune cells have a direct impact on proximal muscle tissue by promoting its progressive replacement by fibrosis via the expression of pro-inflammatory and profibrosing signatures. These data could possibly explain the evolution towards a state of disability for some patients.<\/jats:p>","DOI":"10.3390\/cells12232747","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T07:44:42Z","timestamp":1701330282000},"page":"2747","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Spatial Transcriptomics Reveals Signatures of Histopathological Changes in Muscular Sarcoidosis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6401-8328","authenticated-orcid":false,"given":"Hippolyte","family":"Lequain","sequence":"first","affiliation":[{"name":"D\u00e9partement de M\u00e9decine Interne, H\u00f4pital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France"},{"name":"Institut NeuroMyoG\u00e8ne INMG-PGNM, Physiopathologie et G\u00e9n\u00e9tique du Neurone et du Muscle, UMR5261, Inserm U1315, Facult\u00e9 de M\u00e9decine Rockefeller, Universit\u00e9 Claude Bernard UCBL-Lyon 1, 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"D\u00e9gletagne","sequence":"additional","affiliation":[{"name":"CRCL Core Facilities, Centre de Recherche en Canc\u00e9rologie de Lyon (CRCL) INSERM U1052-CNRS UMR5286, Universit\u00e9 de Lyon, Universit\u00e9 Claude Bernard Lyon1, Centre L\u00e9on B\u00e9rard, 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Streichenberger","sequence":"additional","affiliation":[{"name":"Institut NeuroMyoG\u00e8ne INMG-PGNM, Physiopathologie et G\u00e9n\u00e9tique du Neurone et du Muscle, UMR5261, Inserm U1315, Facult\u00e9 de M\u00e9decine Rockefeller, Universit\u00e9 Claude Bernard UCBL-Lyon 1, 69008 Lyon, France"},{"name":"Service d\u2019Anatomopathologie, Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Valantin","sequence":"additional","affiliation":[{"name":"CRCL Core Facilities, Centre de Recherche en Canc\u00e9rologie de Lyon (CRCL) INSERM U1052-CNRS UMR5286, Universit\u00e9 de Lyon, Universit\u00e9 Claude Bernard Lyon1, Centre L\u00e9on B\u00e9rard, 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Simonet","sequence":"additional","affiliation":[{"name":"Institut NeuroMyoG\u00e8ne INMG-PGNM, Physiopathologie et G\u00e9n\u00e9tique du Neurone et du Muscle, UMR5261, Inserm U1315, Facult\u00e9 de M\u00e9decine Rockefeller, Universit\u00e9 Claude Bernard UCBL-Lyon 1, 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Schaeffer","sequence":"additional","affiliation":[{"name":"Institut NeuroMyoG\u00e8ne INMG-PGNM, Physiopathologie et G\u00e9n\u00e9tique du Neurone et du Muscle, UMR5261, Inserm U1315, Facult\u00e9 de M\u00e9decine Rockefeller, Universit\u00e9 Claude Bernard UCBL-Lyon 1, 69008 Lyon, France"},{"name":"Centre de Biotechnologie Cellulaire, CHU de Lyon\u2014HCL Groupement Est, 69677 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3070-3842","authenticated-orcid":false,"given":"Pascal","family":"S\u00e8ve","sequence":"additional","affiliation":[{"name":"D\u00e9partement de M\u00e9decine Interne, H\u00f4pital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France"},{"name":"P\u00f4le IMER, HESPER EA 7425, 69002 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3214-5880","authenticated-orcid":false,"given":"Pascal","family":"Leblanc","sequence":"additional","affiliation":[{"name":"Institut NeuroMyoG\u00e8ne INMG-PGNM, Physiopathologie et G\u00e9n\u00e9tique du Neurone et du Muscle, UMR5261, Inserm U1315, Facult\u00e9 de M\u00e9decine Rockefeller, Universit\u00e9 Claude Bernard UCBL-Lyon 1, 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"S\u00e8ve, P., Pacheco, Y., Durupt, F., Jamilloux, Y., Gerfaud-Valentin, M., Isaac, S., Boussel, L., Calender, A., Androdias, G., and Valeyre, D. (2021). Sarcoidosis: A Clinical Overview from Symptoms to Diagnosis. Cells, 10.","DOI":"10.3390\/cells10040766"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"788502","DOI":"10.3389\/fimmu.2021.788502","article-title":"The Role of Diverse Immune Cells in Sarcoidosis","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.ccm.2008.03.011","article-title":"Etiology of Sarcoidosis","volume":"29","author":"Chen","year":"2008","journal-title":"Clin. Chest Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.it.2020.01.007","article-title":"Sarcoidosis and the mTOR, Rac1, and Autophagy Triad","volume":"41","author":"Pacheco","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ijmyco.2014.10.008","article-title":"Sarcoidosis: Role of non-tuberculosis mycobacteria and Mycobacterium tuberculosis","volume":"3","author":"Mortaz","year":"2014","journal-title":"Int. J. Mycobacteriol."},{"key":"ref_6","first-page":"e10812","article-title":"The Role of Propionibacterium acnes in the Pathogenesis of Sarcoidosis and Ulcerative Colitis: How This Connection May Inspire Novel Management of These Conditions","volume":"12","author":"Sakhamuru","year":"2020","journal-title":"Cureus"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0140-6736(98)02326-5","article-title":"Macrophagic myofasciitis: An emerging entity","volume":"352","author":"Gherardi","year":"1998","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1111\/nan.12231","article-title":"Th2-M2 immunity in lesions of muscular sarcoidosis and macrophagic myofasciitis: Th2-M2 immunity in lesions","volume":"41","author":"Preusse","year":"2015","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.nmd.2022.05.012","article-title":"Clinical characteristics and outcome in muscular sarcoidosis: A retrospective cohort study and literature review","volume":"32","author":"Raaphorst","year":"2022","journal-title":"Neuromuscul. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.autrev.2014.01.017","article-title":"Diagnosis and classification of granulomatous myositis","volume":"13","author":"Grau","year":"2014","journal-title":"Autoimmun. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e452","DOI":"10.1212\/NXI.0000000000000452","article-title":"Symptomatic muscular sarcoidosis: Lessons from a nationwide multicenter study","volume":"5","author":"Abbara","year":"2018","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_12","first-page":"e910","article-title":"Granulomatosis-associated myositis: High prevalence of sporadic inclusion body myositis","volume":"94","author":"Allenbach","year":"2020","journal-title":"Neurology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.it.2020.04.006","article-title":"Inflammation and Skeletal Muscle Regeneration: Leave It to the Macrophages!","volume":"41","author":"Chazaud","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nm.3896","article-title":"Shifts in macrophage cytokine production drive muscle fibrosis","volume":"21","author":"Tidball","year":"2015","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"eadd9984","DOI":"10.1126\/sciadv.add9984","article-title":"Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis","volume":"9","author":"Coulis","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e26","DOI":"10.1164\/rccm.202002-0251ST","article-title":"Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline","volume":"201","author":"Crouser","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1164\/ajrccm.163.1.9906071","article-title":"Analysis of Intracellular Cytokines in CD4+ and CD8+ Lung and Blood T Cells in Sarcoidosis","volume":"163","author":"Katchar","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"577975","DOI":"10.1016\/j.jneuroim.2022.577975","article-title":"Sarcoidosis, granulomas and myopathy syndromes: A clinical-pathology review","volume":"373","author":"Garret","year":"2022","journal-title":"J. Neuroimmunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Jaiswal, A., Rehman, R., Dutta, J., Singh, S., Ray, A., Shridhar, M., Jaisankar, J., Bhatt, M., Khandelwal, D., and Sahoo, B. (2023). Cellular Distribution of Secreted Phospholipase A2 in Lungs of IPF Patients and Its Inhibition in Bleomycin-Induced Pulmonary Fibrosis in Mice. Cells, 12.","DOI":"10.3390\/cells12071044"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1681\/ASN.2008060628","article-title":"IL-6 and Serum Amyloid A Synergy Mediates Angiotensin II\u2014Induced Muscle Wasting","volume":"20","author":"Zhang","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Langhans, C., Weber-Carstens, S., Schmidt, F., Hamati, J., Kny, M., Zhu, X., Wollersheim, T., Koch, S., Krebs, M., and Schulz, H. (2014). Inflammation-Induced Acute Phase Response in Skeletal Muscle and Critical Illness Myopathy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092048"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11518","DOI":"10.1073\/pnas.89.23.11518","article-title":"Tumor necrosis factor alpha response elements in the HLA-DRA promoter: Identification of a tumor necrosis factor alpha-induced DNA-protein complex in astrocytes","volume":"89","author":"Panek","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2846","DOI":"10.4049\/jimmunol.154.6.2846","article-title":"Class II MHC gene expression in microglia. Regulation by the cytokines IFN-gamma, TNF-alpha, and TGF-beta","volume":"154","author":"Panek","year":"1995","journal-title":"J. Immunol. Baltim."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1056\/NEJMoa1805958","article-title":"Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis","volume":"379","author":"Damsky","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1136\/jcp.41.4.410","article-title":"Skeletal muscle expression of class II histocompatibility antigens (HLA-DR) in polymyositis and other muscle disorders with an inflammatory infiltrate","volume":"41","author":"Zuk","year":"1988","journal-title":"J. Clin. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/S0002-9440(10)62513-8","article-title":"Skeletal Muscle Fibers Express Major Histocompatibility Complex Class II Antigens Independently of Inflammatory Infiltrates in Inflammatory Myopathies","volume":"159","author":"Englund","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1161\/ATVBAHA.112.300569","article-title":"Galectin-3 Mediates Aldosterone-Induced Vascular Fibrosis","volume":"33","author":"Calvier","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1161\/HYPERTENSIONAHA.115.05876","article-title":"Galectin-3 Blockade Inhibits Cardiac Inflammation and Fibrosis in Experimental Hyperaldosteronism and Hypertension","volume":"66","author":"Calvier","year":"2015","journal-title":"Hypertension"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kumagai, K., Tabu, K., Sasaki, F., Takami, Y., Morinaga, Y., Mawatari, S., Hashimoto, S., Tanoue, S., Kanmura, S., and Tamai, T. (2015). Glycoprotein Nonmetastatic Melanoma B (Gpnmb)-Positive Macrophages Contribute to the Balance between Fibrosis and Fibrolysis during the Repair of Acute Liver Injury in Mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0143413"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1172\/JCI37662","article-title":"Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-\u03b2","volume":"119","author":"Vetrone","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3431","DOI":"10.1093\/hmg\/ddz181","article-title":"Spp1 (osteopontin) promotes TGF\u03b2 processing in fibroblasts of dystrophin-deficient muscles through matrix metalloproteinases","volume":"28","author":"Kramerova","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1097\/BOR.0000000000000831","article-title":"Lymphocyte immunophenotyping in inflammatory myositis: A review","volume":"33","author":"Franco","year":"2021","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nm.3869","article-title":"Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro\/adipogenic progenitors","volume":"21","author":"Lemos","year":"2015","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/5584_2014_106","article-title":"TGF-\u03b2 and SMADs mRNA Expression in Pulmonary Sarcoidosis","volume":"Volume 852","author":"Pokorski","year":"2014","journal-title":"Respiratory Carcinogenesis"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ismaeel, A., Kim, J.-S., Kirk, J.S., Smith, R.S., Bohannon, W.T., and Koutakis, P. (2019). Role of Transforming Growth Factor-\u03b2 in Skeletal Muscle Fibrosis: A Review. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102446"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1513\/pats.201203-023AW","article-title":"The Impact of TGF-\u03b2 on Lung Fibrosis: From Targeting to Biomarkers","volume":"9","author":"Fernandez","year":"2012","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1006\/exmp.2001.2376","article-title":"TNF-\u03b1, PDGF, and TGF-\u03b21 Expression by Primary Mouse Bronchiolar-Alveolar Epithelial and Mesenchymal Cells: TNF-\u03b1 Induces TGF-\u03b21","volume":"71","author":"Warshamana","year":"2001","journal-title":"Exp. Mol. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"673404","DOI":"10.3389\/fphys.2021.673404","article-title":"Evolving Roles of Muscle-Resident Fibro-Adipogenic Progenitors in Health, Regeneration, Neuromuscular Disorders, and Aging","volume":"12","author":"Theret","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7058","DOI":"10.1038\/s41467-022-34191-y","article-title":"Depletion of CD206+ M2-like macrophages induces fibro-adipogenic progenitors activation and muscle regeneration","volume":"13","author":"Nawaz","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/j.ajpath.2010.11.065","article-title":"M2 Polarized Macrophages and Giant Cells Contribute to Myofibrosis in Neuromuscular Sarcoidosis","volume":"178","author":"Prokop","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12969-016-0121-5","article-title":"Sarcoidosis presenting as granulomatous myositis in a 16-year-old adolescent","volume":"14","author":"Orandi","year":"2016","journal-title":"Pediatr. Rheumatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e3089","DOI":"10.1097\/MD.0000000000003089","article-title":"Life-Threatening Hypercalcemia Revealing Diffuse and Isolated Acute Sarcoid-Like Myositis: A New Entity? (A Case-Series)","volume":"95","author":"Mageau","year":"2016","journal-title":"Medicine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1016\/S0140-6736(12)60683-7","article-title":"A tiger man","volume":"380","author":"Lhommel","year":"2012","journal-title":"Lancet"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1056\/NEJMra1402225","article-title":"Inflammatory Muscle Diseases","volume":"372","author":"Dalakas","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3233\/JND-180308","article-title":"Current Classification and Management of Inflammatory Myopathies","volume":"5","author":"Schmidt","year":"2018","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.semarthrit.2017.03.005","article-title":"Efficacy and safety of tumor necrosis factor antagonists in refractory sarcoidosis: A multicenter study of 132 patients","volume":"47","author":"Jamilloux","year":"2017","journal-title":"Semin. Arthritis Rheum."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/23\/2747\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:34:50Z","timestamp":1760132090000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/23\/2747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,30]]},"references-count":46,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["cells12232747"],"URL":"https:\/\/doi.org\/10.3390\/cells12232747","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,30]]}}}