{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T23:26:42Z","timestamp":1768692402901,"version":"3.49.0"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,18]],"date-time":"2022-04-18T00:00:00Z","timestamp":1650240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science KAKENHI (KAKENHI \u201cC\u201d)","award":["20K07420"],"award-info":[{"award-number":["20K07420"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In our previous study, we revealed the ameliorative therapeutic effect of dexamethasone (Dex) for Lupus nephritis lesions in the MRL\/MpJ-Fas lpr\/lpr (Lpr) mouse model. The female Lpr mice developed a greater number of mediastinal fat-associated lymphoid clusters (MFALCs) and inflammatory lung lesions compared to the male mice. However, the effect of Dex, an immunosuppressive drug, on both lung lesions and the development of MFALCs in Lpr mice has not been identified yet. Therefore, in this study, we compared the development of lung lesions and MFALCs in female Lpr mice that received either saline (saline group \u201cSG\u201d) or dexamethasone (dexamethasone group \u201cDG\u201d) in drinking water as a daily dose along with weekly intraperitoneal injections for 10 weeks. Compared to the SG group, the DG group showed a significant reduction in the levels of serum anti-dsDNA antibodies, the size of MFALCs, the degree of lung injury, the area of high endothelial venules (HEVs), and the number of proliferating and immune cells in both MFALCs and the lungs. A significant positive correlation was observed between the size of MFALCs and the cellular aggregation in the lungs of Lpr mice. Therefore, this study confirmed the ameliorative effect of Dex on the development of lung injury and MFALCs via their regressive effect on both immune cells\u2019 proliferative activity and the development of HEVs. Furthermore, the reprogramming of MFALCs by targeting immune cells and HEVs may provide a therapeutic strategy for autoimmune-disease-associated lung injury.<\/jats:p>","DOI":"10.3390\/ijms23084449","type":"journal-article","created":{"date-parts":[[2022,4,18]],"date-time":"2022-04-18T22:04:02Z","timestamp":1650319442000},"page":"4449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Ameliorative Effect of Dexamethasone on the Development of Autoimmune Lung Injury and Mediastinal Fat-Associated Lymphoid Clusters in an Autoimmune Disease Mouse Model"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7347-4587","authenticated-orcid":false,"given":"Yaser Hosny Ali","family":"Elewa","sequence":"first","affiliation":[{"name":"Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Hokkaido 060-0818, Japan"},{"name":"Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md Abdul","family":"Masum","sequence":"additional","affiliation":[{"name":"Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Hokkaido 060-0818, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4226-2423","authenticated-orcid":false,"given":"Sherif Kh. A.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md Rashedul","family":"Islam","sequence":"additional","affiliation":[{"name":"Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Hokkaido 060-0818, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3204-0245","authenticated-orcid":false,"given":"Teppei","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Hokkaido 060-0818, Japan"},{"name":"Department of Biological Safety Research, Chitose Laboratory, Japan Food Research Laboratories, Hokkaido 066-0052, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6643-1554","authenticated-orcid":false,"given":"Osamu","family":"Ichii","sequence":"additional","affiliation":[{"name":"Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Hokkaido 060-0818, Japan"},{"name":"Laboratory of Agrobiomedical Science, Faculty of Agriculture, Hokkaido University, Hokkaido 060-0818, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Kon","sequence":"additional","affiliation":[{"name":"Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Hokkaido 060-0818, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,18]]},"reference":[{"key":"ref_1","first-page":"e8094","article-title":"The Prevalence of Autoimmune Disorders in Women: A Narrative Review","volume":"12","author":"Angum","year":"2020","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1056\/NEJM199005033221805","article-title":"Rheumatoid arthritis. Pathophysiology and implications for therapy","volume":"322","author":"Harris","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/S0140-6736(07)60750-8","article-title":"Inflammatory bowel disease: Cause and immunobiology","volume":"369","author":"Baumgart","year":"2007","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1111\/j.1365-2230.2006.02150.x","article-title":"Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis","volume":"31","author":"Wenzel","year":"2006","journal-title":"Clin. Exp. Dermatol. Exp. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1080\/00981389.2012.683369","article-title":"Systemic Lupus Erythematosus: An Overview","volume":"51","author":"Askanase","year":"2012","journal-title":"Soc. Work Health Care"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1097\/01.mcp.0000170522.71497.61","article-title":"Autoimmunity and interstitial lung disease","volume":"11","author":"Jindal","year":"2005","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"600","DOI":"10.2353\/ajpath.2008.071008","article-title":"Sex differences in autoimmune disease from a pathological perspective","volume":"173","author":"Fairweather","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.cvsm.2010.02.003","article-title":"Autoimmune diseases in small animals","volume":"40","author":"Gershwin","year":"2010","journal-title":"Vet. Clin. Small Anim. Pract."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1385\/IR:25:2:143","article-title":"Use of genetic knockouts to modulate disease expression in a murine model of lupus, MRL\/lpr mice","volume":"25","author":"Reilly","year":"2002","journal-title":"Immunol. Res."},{"key":"ref_10","first-page":"271694","article-title":"Murine models of systemic lupus erythematosus","volume":"2011","author":"Perry","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/imm.12539","article-title":"Comparative analysis of mediastinal fat-associated lymphoid cluster development and lung cellular infiltration in murine autoimmune disease models and the corresponding normal control strains","volume":"147","author":"Elewa","year":"2016","journal-title":"Immunology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1165\/rcmb.2011-0392TR","article-title":"Role of chemokines in the pathogenesis of acute lung injury","volume":"46","author":"Bhatia","year":"2012","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Klimatcheva, E., Pandina, T., Reilly, C., Torno, S., Bussler, H., Scrivens, M., Jonason, A., Mallow, C., Doherty, M., and Paris, M. (2015). CXCL13 antibody for the treatment of autoimmune disorders. BMC Immunol., 16.","DOI":"10.1186\/s12865-015-0068-1"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kameda, M., Otsuka, M., Chiba, H., Kuronuma, K., Hasegawa, T., Takahashi, H., and Takahashi, H. (2020). CXCL9, CXCL10, and CXCL11; biomarkers of pulmonary inflammation associated with autoimmunity in patients with collagen vascular diseases-associated interstitial lung disease and interstitial pneumonia with autoimmune features. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0241719"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14","DOI":"10.29245\/2578-3009\/2019\/4.1178","article-title":"Immunosuppressive drugs in organ transplantation to prevent allograft rejection: Mode of action and side effects","volume":"3","author":"Claeys","year":"2019","journal-title":"J. Immunol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Horby, P., Lim, W.S., Emberson, J., Mafham, M., Bell, J., Linsell, L., Staplin, N., Brightling, C., Ustianowski, A., and Elmahi, E. (2020). Effect of Dexamethasone in Hospitalized Patients with COVID-19\u2014Preliminary Report. medRxiv.","DOI":"10.1101\/2020.06.22.20137273"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3211","DOI":"10.3389\/fimmu.2020.595672","article-title":"Vasculature-Associated Lymphoid Tissue: A Unique Tertiary Lymphoid Tissue Correlates with Renal Lesions in Lupus Nephritis Mouse Model","volume":"11","author":"Masum","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1080\/08916934.2017.1344973","article-title":"Sex-related differences in autoimmune-induced lung lesions in MRL\/MpJ-faslpr mice are mediated by the development of mediastinal fat-associated lymphoid clusters","volume":"50","author":"Elewa","year":"2017","journal-title":"Autoimmunity"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3389\/fimmu.2018.00271","article-title":"Histopathological Correlations between Mediastinal Fat-Associated Lymphoid Clusters and the Development of Lung Inflammation and Fibrosis following Bleomycin Administration in Mice","volume":"9","author":"Elewa","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1017\/S1431927620024824","article-title":"Pathological Alternations of Mediastinal Fat-Associated Lymphoid Cluster and Lung in a Streptozotocin-Induced Diabetic Mouse Model","volume":"27","author":"Elewa","year":"2021","journal-title":"Microsc. Microanal."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ctrv.2017.11.007","article-title":"CXCL9, CXCL10, CXCL11\/CXCR3 axis for immune activation\u2014A target for novel cancer therapy","volume":"63","author":"Tokunaga","year":"2018","journal-title":"Cancer Treat. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.ajpath.2014.10.003","article-title":"CXCL9 is important for recruiting immune T cells into the brain and inducing an accumulation of the T cells to the areas of tachyzoite proliferation to prevent reactivation of chronic cerebral infection with Toxoplasma gondii","volume":"185","author":"Ochiai","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1084\/jem.187.4.655","article-title":"B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1\/CXCR5","volume":"187","author":"Legler","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.21037\/tcr.2018.11.26","article-title":"Clinical significance of CXCL13\/CXCR5 axis in human cancers","volume":"7","author":"Zhu","year":"2018","journal-title":"Transl. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mokra, D., Mikolka, P., Kosutova, P., and Mokry, J. (2019). Corticosteroids in Acute Lung Injury: The Dilemma Continues. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194765"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5762","DOI":"10.1038\/s41598-021-85539-1","article-title":"Corticosteroid responsiveness in patients with acute exacerbation of interstitial lung disease admitted to the emergency department","volume":"11","author":"Jang","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1056\/NEJMoa2021436","article-title":"Dexamethasone in Hospitalized Patients with Covid-19","volume":"384","author":"Horby","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1186\/s13063-020-04643-1","article-title":"Efficacy of dexamethasone treatment for patients with the acute respiratory distress syndrome caused by COVID-19: Study protocol for a randomized controlled superiority trial","volume":"21","author":"Villar","year":"2020","journal-title":"Trials"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"491","DOI":"10.3389\/fimmu.2016.00491","article-title":"High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation","volume":"7","author":"Ruddle","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"471","DOI":"10.3389\/fendo.2019.00471","article-title":"CXCL13 and Its Receptor CXCR5 in Cancer: Inflammation, Immune Response, and Beyond","volume":"10","author":"Kazanietz","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1006\/cyto.2001.0923","article-title":"Human B Cell-Attracting Chemokine 1 (Bca-1; Cxcl13) Is an Agonist for the Human Cxcr3 Receptor","volume":"15","author":"Jenh","year":"2001","journal-title":"Cytokine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1186\/s40425-019-0757-z","article-title":"IL-17 inhibits CXCL9\/10-mediated recruitment of CD8+ cytotoxic T cells and regulatory T cells to colorectal tumors","volume":"7","author":"Chen","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1007\/s00011-020-01378-2","article-title":"Macrophage polarization and its role in the pathogenesis of acute lung injury\/acute respiratory distress syndrome","volume":"69","author":"Chen","year":"2020","journal-title":"Inflamm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s12026-012-8291-9","article-title":"Macrophage polarization and plasticity in health and disease","volume":"53","author":"Biswas","year":"2012","journal-title":"Immunol. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"L709","DOI":"10.1152\/ajplung.00341.2013","article-title":"Diverse macrophage populations mediate acute lung inflammation and resolution","volume":"306","author":"Aggarwal","year":"2014","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.immuni.2010.05.007","article-title":"Alternative activation of macrophages: Mechanism and functions","volume":"32","author":"Gordon","year":"2010","journal-title":"Immunity"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2119\/molmed.2010.00138","article-title":"Contribution of neutrophils to acute lung injury","volume":"17","author":"Grommes","year":"2011","journal-title":"Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"104881","DOI":"10.1016\/j.phrs.2020.104881","article-title":"Granulocyte-targeted therapies for airway diseases","volume":"157","author":"Tavares","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1146\/annurev.immunol.25.022106.141647","article-title":"Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators and pathways","volume":"25","author":"Serhan","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/j.1365-3083.1982.tb00698.x","article-title":"Thymic influences on autoimmunity in MRL-lpr mice","volume":"16","author":"Wofsy","year":"1982","journal-title":"Scand. J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/1465-9921-12-131","article-title":"Attenuation of lung inflammation and fibrosis in CD69-deficient mice after intratracheal bleomycin","volume":"12","author":"Yamauchi","year":"2011","journal-title":"Respir. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"333","DOI":"10.2147\/ITT.S279228","article-title":"Acetylcholine Regulates Pulmonary Pathology During Viral Infection and Recovery","volume":"9","author":"Horkowitz","year":"2020","journal-title":"ImmunoTargets Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.jcpa.2014.07.003","article-title":"Immunohistochemical expression of ionized calcium binding adapter molecule 1 in cutaneous histiocytic proliferative, neoplastic and inflammatory disorders of dogs and cats","volume":"151","author":"Pierezan","year":"2014","journal-title":"J. Comp. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.neo.2019.01.005","article-title":"Prognostic Value of Macrophage Phenotypes in Resectable Non-Small Cell Lung Cancer Assessed by Multiplex Immunohistochemistry","volume":"21","author":"Rakaee","year":"2019","journal-title":"Neoplasia"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Nakamura, T., Ichii, O., Sunden, Y., Elewa, Y.H.A., Yoshiyasu, T., Hattori, H., Tatsumi, O., Kon, Y., and Nagasaki, K.-I. (2019). Slc:Wistar\/ST rats develop unilateral thyroid dysgenesis: A novel animal model of thyroid hemiagenesis. 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