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• W3154606485 abstract "•Human and mouse ADSCs express IL-33 in response to IL-β stimulation•mADSC-derived IL-33 inhibits inflammation in salivary glands in SS model•mADSC-derived IL-33 expand ST2+ Tregs in vitro and in SS model Adipose-derived mesenchymal stromal cells (ADSCs) play important roles in the alleviation of inflammation and autoimmune diseases. Interleukin-33 (IL-33), a member of the IL-1 family, has been shown to regulate innate and adaptive immunity. However, it is still unknown whether ADSCs regulate immune responses via IL-33. We show here that ADSCs produced IL-33 in response to IL-1β stimulation, which depended on TAK1, ERK, and p38 pathways. ADSCs-derived IL-33 drove the proliferation of CD4+Foxp3+ST2+ regulatory T cells (Tregs) and alleviated experimental autoimmune Sjögren syndrome in mice. Importantly, human ADSCs also produced IL-33 in response to IL-1β. Thus, we have revealed a previously unrecognized immunoregulatory function of ADSCs by IL-33 production in experimental autoimmunity, which may have clinical applications for human immunopathology. Adipose-derived mesenchymal stromal cells (ADSCs) play important roles in the alleviation of inflammation and autoimmune diseases. Interleukin-33 (IL-33), a member of the IL-1 family, has been shown to regulate innate and adaptive immunity. However, it is still unknown whether ADSCs regulate immune responses via IL-33. We show here that ADSCs produced IL-33 in response to IL-1β stimulation, which depended on TAK1, ERK, and p38 pathways. ADSCs-derived IL-33 drove the proliferation of CD4+Foxp3+ST2+ regulatory T cells (Tregs) and alleviated experimental autoimmune Sjögren syndrome in mice. Importantly, human ADSCs also produced IL-33 in response to IL-1β. Thus, we have revealed a previously unrecognized immunoregulatory function of ADSCs by IL-33 production in experimental autoimmunity, which may have clinical applications for human immunopathology. Adipose-derived mesenchymal stromal cells (ADSCs), a subtype of mesenchymal stromal cells (MSCs), played important roles in regenerative medicine to differentiating in bone and adipocytes and in modulating immune responses and alleviating inflammation or autoimmune diseases including arthritis, colitis, and autoimmune diabetes (Bassi et al., 2012Bassi E.J. Moraes-Vieira P.M. Moreira-Sa C.S. Almeida D.C. Vieira L.M. Cunha C.S. Hiyane M.I. Basso A.S. Pacheco-Silva A. Camara N.O. Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes.Diabetes. 2012; 61: 2534-2545Crossref PubMed Scopus (89) Google Scholar; Gonzalez et al., 2009aGonzalez M.A. Gonzalez-Rey E. Rico L. Buscher D. Delgado M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses.Gastroenterology. 2009; 136: 978-989Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar, Gonzalez et al., 2009bGonzalez M.A. Gonzalez-Rey E. Rico L. Buscher D. Delgado M. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells.Arthritis Rheum. 2009; 60: 1006-1019Crossref PubMed Scopus (393) Google Scholar; Mizuno et al., 2012Mizuno H. Tobita M. Uysal A.C. Concise review: adipose-derived stem cells as a novel tool for future regenerative medicine.Stem Cells. 2012; 30: 804-810Crossref PubMed Scopus (485) Google Scholar; Razmkhah et al., 2015Razmkhah M. Abedi N. Hosseini A. Imani M.T. Talei A.R. Ghaderi A. Induction of T regulatory subsets from naive CD4+ T cells after exposure to breast cancer adipose derived stem cells.Iran. J. Immunol. 2015; 12: 1-15PubMed Google Scholar; Shang et al., 2015Shang Q. Bai Y. Wang G. Song Q. Guo C. Zhang L. Wang Q. Delivery of adipose-derived stem cells attenuates adipose tissue inflammation and insulin resistance in obese mice through remodeling macrophage phenotypes.Stem Cells Dev. 2015; 24: 2052-2064Crossref PubMed Scopus (36) Google Scholar; Zuk et al., 2001Zuk P. Zhu M. Mizuno H. Huang J. Futrell J. Katz A. Benhaim P. Lorenz H. Hedrick M. Multilineage cells from human adipose tissue: implications for cell-based therapies.Tissue Eng. 2001; 7: 211-228Crossref PubMed Scopus (6031) Google Scholar). The MSCs-tracking analysis showed that exogenously delivered MSCs could be detected in inflamed zones for the first week after injection, suggesting their interaction with inflammatory cells and cytokines. Indeed, studies reported that inflammatory cytokines such as interferon (IFN)-γ, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α could be critical for MSC-mediated immunoregulation (Castelo-Branco et al., 2012Castelo-Branco M.T. Soares I.D. Lopes D.V. Buongusto F. Martinusso C.A. do Rosario Jr., A. Souza S.A. Gutfilen B. Fonseca L.M. Elia C. et al.Intraperitoneal but not intravenous cryopreserved mesenchymal stromal cells home to the inflamed colon and ameliorate experimental colitis.PLoS One. 2012; 7: e33360Crossref PubMed Scopus (97) Google Scholar; Chen et al., 2013Chen Q.Q. Yan L. Wang C.Z. Wang W.H. Shi H. Su B.B. Zeng Q.H. Du H.T. Wan J. Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses.World J. Gastroenterol. 2013; 19: 4702-4717Crossref PubMed Scopus (82) Google Scholar; Tanaka et al., 2008Tanaka F. Tominaga K. Ochi M. Tanigawa T. Watanabe T. Fujiwara Y. Ohta K. Oshitani N. Higuchi K. Arakawa T. Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats.Life Sci. 2008; 83: 771-779Crossref PubMed Scopus (104) Google Scholar; Xu et al., 2012Xu J. Wang D. Liu D. Fan Z. Zhang H. Liu O. Ding G. Gao R. Zhang C. Ding Y. et al.Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjogren syndrome.Blood. 2012; 120: 3142-3151Crossref PubMed Scopus (167) Google Scholar). The inflammatory cytokines drive the immunosuppression function of MSCs through expression and release of different factors and cytokines in the inflammatory “niches” (Krampera et al., 2006Krampera M. Cosmi L. Angeli R. Pasini A. Liotta F. Andreini A. Santarlasci V. Mazzinghi B. Pizzolo G. Vinante F. et al.Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells.Stem Cells. 2006; 24: 386-398Crossref PubMed Scopus (1001) Google Scholar; Meisel et al., 2004Meisel R. Zibert A. Laryea M. Gobel U. Daubener W. Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation.Blood. 2004; 103: 4619-4621Crossref PubMed Scopus (1311) Google Scholar; Mougiakakos et al., 2011Mougiakakos D. Jitschin R. Johansson C.C. Okita R. Kiessling R. Le Blanc K. The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells.Blood. 2011; 117: 4826-4835Crossref PubMed Scopus (166) Google Scholar; Ren et al., 2008Ren G. Zhang L. Zhao X. Xu G. Zhang Y. Roberts A.I. Zhao R.C. Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide.Cell Stem Cell. 2008; 2: 141-150Abstract Full Text Full Text PDF PubMed Scopus (1410) Google Scholar, Ren et al., 2009Ren G. Su J. Zhang L. Zhao X. Ling W. L'Huillie A. Zhang J. Lu Y. Roberts A.I. Ji W. et al.Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression.Stem Cells. 2009; 27: 1954-1962Crossref PubMed Scopus (437) Google Scholar; Sheng et al., 2008Sheng H. Wang Y. Jin Y. Zhang Q. Zhang Y. Wang L. Shen B. Yin S. Liu W. Cui L. et al.A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1.Cell Res. 2008; 18: 846-857Crossref PubMed Scopus (282) Google Scholar). IL-33 was first reported as a novel member of the IL-1 family in 2005 (Schmitz et al., 2005Schmitz J. Owyang A. Oldham E. Song Y. Murphy E. McClanahan T.K. Zurawski G. Moshrefi M. Qin J. Li X. et al.IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines.Immunity. 2005; 23: 479-490Abstract Full Text Full Text PDF PubMed Scopus (2604) Google Scholar) and is now recognized as a crucial factor in influencing innate and adaptive immunity (Ali et al., 2011Ali S. Mohs A. Thomas M. Klare J. Ross R. Schmitz M.L. Martin M.U. The dual function cytokine IL-33 interacts with the transcription factor NF-kappaB to dampen NF-kappaB-stimulated gene transcription.J. Immunol. 2011; 187: 1609-1616Crossref PubMed Scopus (224) Google Scholar). Among its pleiotropic functions (Baumann et al., 2015Baumann C. Bonilla W.V. Frohlich A. Helmstetter C. Peine M. Hegazy A.N. Pinschewer D.D. Lohning M. T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses.Proc. Natl. Acad. Sci. U S A. 2015; 112: 4056-4061Crossref PubMed Scopus (95) Google Scholar; Gao et al., 2015Gao X. Wang X. Yang Q. Zhao X. Wen W. Li G. Lu J. Qin W. Qi Y. Xie F. et al.Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells.J. Immunol. 2015; 194: 438-445Crossref PubMed Scopus (137) Google Scholar; Hepworth et al., 2012Hepworth M.R. Maurer M. Hartmann S. Regulation of type 2 immunity to helminths by mast cells.Gut Microbes. 2012; 3: 476-481Crossref PubMed Scopus (32) Google Scholar; Price et al., 2010Price A.E. Liang H.E. Sullivan B.M. Reinhardt R.L. Eisley C.J. Erle D.J. Locksley R.M. Systemically dispersed innate IL-13-expressing cells in type 2 immunity.Proc. Natl. Acad. Sci. U S A. 2010; 107: 11489-11494Crossref PubMed Scopus (815) Google Scholar; Reichenbach et al., 2015Reichenbach D.K. Schwarze V. Matta B.M. Tkachev V. Lieberknecht E. Liu Q. Koehn B.H. Pfeifer D. Taylor P.A. Prinz G. et al.The IL-33/ST2 axis augments effector T-cell responses during acute GVHD.Blood. 2015; 125: 3183-3192Crossref PubMed Scopus (98) Google Scholar; Yang et al., 2011Yang Q. Li G. Zhu Y. Liu L. Chen E. Turnquist H. Zhang X. Finn O.J. Chen X. Lu B. IL-33 synergizes with TCR and IL-12 signaling to promote the effector function of CD8+ T cells.Eur. J. Immunol. 2011; 41: 3351-3360Crossref PubMed Scopus (132) Google Scholar), IL-33 drives proliferation of CD4+Foxp3+ regulatory T cells (Tregs) and group 2 innate lymphoid cells (ILC2s) and regulates immune responses in lymphoid organs, gut, lungs, and adipose tissues (Arpaia et al., 2015Arpaia N. Green J.A. Moltedo B. Arvey A. Hemmers S. Yuan S. Treuting P.M. Rudensky A.Y. A distinct function of regulatory T cells in tissue protection.Cell. 2015; 162: 1078-1089Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar; Matta et al., 2016Matta B.M. Reichenbach D.K. Zhang X. Mathews L. Koehn B.H. Dwyer G.K. Lott J.M. Uhl F.M. Pfeifer D. Feser C.J. et al.Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD.Blood. 2016; 128: 427-439Crossref PubMed Scopus (61) Google Scholar; Molofsky et al., 2015bMolofsky A.B. Van Gool F. Liang H.E. Van Dyken S.J. Nussbaum J.C. Lee J. Bluestone J.A. Locksley R.M. Interleukin-33 and interferon-gamma counter-regulate group 2 innate lymphoid cell activation during immune perturbation.Immunity. 2015; 43: 161-174Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar; Mougiakakos et al., 2011Mougiakakos D. Jitschin R. Johansson C.C. Okita R. Kiessling R. Le Blanc K. The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells.Blood. 2011; 117: 4826-4835Crossref PubMed Scopus (166) Google Scholar; Schiering et al., 2014Schiering C. Krausgruber T. Chomka A. Frohlich A. Adelmann K. Wohlfert E.A. Pott J. Griseri T. Bollrath J. Hegazy A.N. et al.The alarmin IL-33 promotes regulatory T-cell function in the intestine.Nature. 2014; 513: 564-568Crossref PubMed Scopus (574) Google Scholar). IL-33 also functions for the maintenance of tissue homeostasis and repair of tissue damage (Liew et al., 2016Liew F.Y. Girard J.P. Turnquist H.R. Interleukin-33 in health and disease.Nat. Rev. Immunol. 2016; 16: 676-689Crossref PubMed Scopus (474) Google Scholar; Molofsky et al., 2015aMolofsky A.B. Savage A.K. Locksley R.M. Interleukin-33 in tissue homeostasis, injury, and inflammation.Immunity. 2015; 42: 1005-1019Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar). Typically IL-33 is expressed at high levels in the nuclei of various cell types in human and mouse tissues in the steady state, including endothelial cells (Chen et al., 2015Chen W.Y. Hong J. Gannon J. Kakkar R. Lee R.T. Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33.Proc. Natl. Acad. Sci. U S A. 2015; 112: 7249-7254Crossref PubMed Scopus (86) Google Scholar), epithelial cells (Nakanishi et al., 2013Nakanishi W. Yamaguchi S. Matsuda A. Suzukawa M. Shibui A. Nambu A. Kondo K. Suto H. Saito H. Matsumoto K. et al.IL-33, but not IL-25, is crucial for the development of house dust mite antigen-induced allergic rhinitis.PLoS One. 2013; 8: e78099Crossref PubMed Scopus (36) Google Scholar), macrophages, and fibroblast-like cells (Moussion et al., 2008Moussion C. Ortega N. Girard J.P. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'?.PLoS One. 2008; 3: e3331Crossref PubMed Scopus (813) Google Scholar; Pichery et al., 2012Pichery M. Mirey E. Mercier P. Lefrancais E. Dujardin A. Ortega N. Girard J.P. Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain.J. Immunol. 2012; 188: 3488-3495Crossref PubMed Scopus (305) Google Scholar). Besides, it was recently reported that some subsets of MSCs expressing IL-33 were involved in the homeostasis and metabolism of adipocytes (Mahlakoiv et al., 2019Mahlakoiv T. Flamar A.L. Johnston L.K. Moriyama S. Putzel G.G. Bryce P.J. Artis D. Stromal cells maintain immune cell homeostasis in adipose tissue via production of interleukin-33.Sci. Immunol. 2019; 4: eaax0416Crossref PubMed Scopus (78) Google Scholar). However, it remains largely unknown what drives MSCs to produce IL-33 and whether the IL-33 has immunoregulatory effects on distant organs and tissues beyond adipose tissues. ADSCs from C57BL/6 mice and IL-33-deficient mice (C57BL/6J-Il33tm1b(EUCOMM)Cln, Il33−/−) were isolated from subcutaneous fat tissues. ADSCs were determined based on their positivity for MSC markers SCA-1, CD44, CD90, and CD105 and negativity for epithelial cell marker CD31 and hematopoietic cell marker CD45 (Bourin et al., 2013Bourin P. Bunnell B.A. Casteilla L. Dominici M. Katz A.J. March K.L. Redl H. Rubin J.P. Yoshimura K. Gimble J.M. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT).Cytotherapy. 2013; 15: 641-648Abstract Full Text Full Text PDF PubMed Scopus (1044) Google Scholar) (Figure S1A). Also, ADSCs were functionally capable of differentiating into adipocytes, osteoblasts, and chondroblasts under standard differentiation culture conditions (Figure S1B). ADSCs exhibited no difference in their surface markers and multiple differentiation potential from wild-type (WT) and Il33−/− mice. To mimic IL-33 production from mADSCs in the inflammatory “niches,” we stimulated ADSCs that were isolated from C57BL/6 mice with a panel of inflammatory cytokines in cultures for 6 h Il33 mRNA was determined by real-time PCR. Among the comprehensive panel of the cytokines we examined, only IL-1β was able to significantly upregulate Il33 mRNA expression in ADSCs (Figure 1A). ADSCs expressed spontaneous base levels of Il33 mRNA higher than did T cells (Figure 1B). IL-1β driving Il33 mRNA expression in ADSCs was dose-dependent and reached a plateau at 0.2 ng/mL of IL-1β (Figure 1C). Consistent with Il33 mRNA, western blot analysis showed a substantially higher level of IL-33 protein in IL-1β-treated ADSCs compared with untreated cells (Figure 1D). ELISA analysis also showed higher levels of IL-33 protein in the cell lysates from IL-1β-treated ADSCs when compared with the untreated cells, although IL-33 was hardly detected in the cell culture supernatants from all the cultures (Figure 1E). Of note, although IFN-γ alone was unable to induce Il33 mRNA, it enhanced IL-β-induced IL-33 in mouse ADSCs (Figure S2). Thus, mADSCs produce IL-33 upon IL-1β stimulation. We next investigated the signaling pathways by which IL-33 was induced by IL-1β stimulation in ADSCs. We first analyzed the expression and activation of ERK, p38, JNK, and nuclear factor (NF)-κB proteins in ADSCs stimulated with IL-1β. We found that the relative ratio of phosphorylated ERK (p-ERK)/ERK and phosphorylated p38 (p-p38)/p38 were increased in ADSCs treated with IL-1β compared with the untreated cells (Figure 2A). However, there were no significant differences between the phosphorylated JNK and NF-κB (p65) proteins between IL-1β-treated and untreated ADSCs (Figures S3A and S3B). Next, we investigated which of the aforementioned pathways was involved in IL-1β-driven IL-33 induction in ADSCs by utilizing the selective protein kinase inhibitors 0.2 μM U0126 (for ERK), 20 μM SB203580 (for p38 MAPK), 2 μM SP600125 (for JNK), and 2 μM JSH23 (for NF-κB) to block the activity of the indicated proteins. We found that inhibition of ERK and p38 MAPK activity significantly reduced IL-1β-induced Il33 mRNA and IL-33 protein (Figures 2B and 2D), whereas inhibition of JNK and NF-κB failed to do so (Figures S3C and S3D). In addition, suppression of TAK1 activity also decreased Il33 mRNA and IL-33 protein in ADSCs (Figures 2C and 2D). To explore the mechanism of the TAK1 signal pathway during IL-1β-driven IL-33, we examined whether TAK1 inhibition affects the phosphorylation of p38 and ERK. Our result showed that the phosphorylation of p38 and ERK was significantly reduced in TAK1 inhibitor (100 nM) group after IL-1β treatment (Figure 2E). These data suggest that IL-1β activates TAK1, up-regulating phosphorylation of p38 and ERK, and subsequently mediates IL-33 expression. To determine the immunoregulatory function of IL-33 produced by ADSCs, we next studied the effects of IL-1β-treated mADSCs lysates on CD4+CD25+Foxp3+ Tregs (Chen et al., 2003Chen W. Jin W. Hardegen N. Lei K.J. Li L. Marinos N. McGrady G. Wahl S.M. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.J. Exp. Med. 2003; 198: 1875-1886Crossref PubMed Scopus (3602) Google Scholar), because IL-33 has been shown to promote the proliferation of Tregs (Matta et al., 2016Matta B.M. Reichenbach D.K. Zhang X. Mathews L. Koehn B.H. Dwyer G.K. Lott J.M. Uhl F.M. Pfeifer D. Feser C.J. et al.Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD.Blood. 2016; 128: 427-439Crossref PubMed Scopus (61) Google Scholar; Vasanthakumar et al., 2015Vasanthakumar A. Moro K. Xin A. Liao Y. Gloury R. Kawamoto S. Fagarasan S. Mielke L.A. Afshar-Sterle S. Masters S.L. et al.The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells.Nat. Immunol. 2015; 16: 276-285Crossref PubMed Scopus (313) Google Scholar). ADSCs from WT or Il33−/− mice were cultured with or without IL-1β to confirm that Il33 mRNA and IL-33 protein were detected only in WT but not Il33−/− cells (Figures 3A and 3B ). CD4+CD25+ Tregs isolated from spleen and lymph nodes in C57BL/6 mice were cultured with IL-1β-stimulated WT or Il33−/− ADSCs lysates. We found that IL-1β-stimulated WT ADSCs lysates significantly upregulated Il1rl1 mRNA (receptor for IL-33, ST2) expression in Tregs, which was abrogated by the inclusion of anti-IL-33 antibody in the cultures (Figure 3C). Consistently, IL-1β-stimulated Il33−/− ADSCs lysates exhibited significantly lower activity to upregulate Il1rl1 mRNA in Tregs than did WT ADSCs lysates (Figure 3C). Consequently, the frequency and the absolute number of ST2+ Treg subsets within the CD4+Foxp3+ Tregs cultured with IL-1β-treated WT ADSCs were much higher than those of ST2+ Treg subsets in Tregs treated with Il33−/− ADSCs (Figures 3D and 3E). Consistently, the increase in ST2+ Tregs in Tregs stimulated with WT ADSCs was entirely abolished by neutralization of IL-33 with anti-IL33 antibody (Figure 3E). The data collectively indicate that IL-33 from mADSCs upregulates ST2+ Tregs in cultures. The expansion of ST2+ Tregs by ADSCs-derived IL-33 encouraged us to investigate the immunoregulatory and therapeutic function of ADSCs in autoimmunity and inflammation in vivo. For this, we intravenously injected WT and Il33−/− mADSCs (both on C57BL/6 background) into allogeneic NOD/ShiLtj mice (NOD, on Cataract Shionogi background) that have been well known to develop an autoimmune Sjögren syndrome (SS) spontaneously. The rationale underlying the utilization of allogeneic ADSC transplantation was based on the published animal and clinical studies that show negligible allorejection and side effects of allogeneic MSCs transplantation due to the non/low MHC II expression on MSCs, yet exhibition of beneficial and immunoregulatory function (Alexeev et al., 2014Alexeev V. Arita M. Donahue A. Bonaldo P. Chu M.L. Igoucheva O. Human adipose-derived stem cell transplantation as a potential therapy for collagen VI-related congenital muscular dystrophy.Stem Cell Res. Ther. 2014; 5: 21Crossref PubMed Scopus (33) Google Scholar; Xu et al., 2012Xu J. Wang D. Liu D. Fan Z. Zhang H. Liu O. Ding G. Gao R. Zhang C. Ding Y. et al.Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjogren syndrome.Blood. 2012; 120: 3142-3151Crossref PubMed Scopus (167) Google Scholar). We injected allogeneic ADSCs from WT or Il33−/− mice or PBS into NOD/ShiLtj mice at 7 weeks of age when the inflammation starts to occur in the submandibular glands. Yet, the secretory function of the submandibular glands has not been compromised (Delaleu et al., 2011Delaleu N. Nguyen C.Q. Peck A.B. Jonsson R. Sjogren's syndrome: studying the disease in mice.Arthritis Res. Ther. 2011; 13: 217Crossref PubMed Scopus (71) Google Scholar). The saliva flow rates were measured weekly from 7 through 13 weeks (Figure S4A). We found that WT ADSCs transplantation significantly improved the saliva flow rates 2 weeks after injection in NOD/ShiLtj mice compared with PBS- or Il33−/− mADSCs-treated mice (Figure 4A). We then examined the expression of genes, including Slc12a2, Tjp1, Aqp5, Itpr3, Trpv4, and Chrm3, which have been known to be relevant to submandibular gland function at the 13th week (Markadieu and Delpire, 2014Markadieu N. Delpire E. Physiology and pathophysiology of SLC12A1/2 transporters.Pflugers Arch. 2014; 466: 91-105Crossref PubMed Scopus (74) Google Scholar; Wang et al., 2017Wang S.Q. Wang Y.X. Hua H. Characteristics of labial gland mesenchymal stem cells of healthy individuals and patients with Sjogren's syndrome: a preliminary study.Stem Cells Dev. 2017; 26: 1171-1185Crossref PubMed Scopus (7) Google Scholar). The expressions of all those genes except Aqp5 mRNA in submandibular glands were significantly increased in WT ADSCs-treated mice compared with the mice treated with Il33−/− mADSCs or PBS (Figures 4B–4G). Consistent with the improvement of saliva flow and the upregulation of the genes associated with submandibular gland function, histological analysis of the submandibular gland tissues revealed that transplantation of WT ADSCs resulted in a substantial reduction of inflammatory areas in the submandibular glands compared with Il33−/− ADSCs- or PBS-treated groups (Figures 4H and 4I). These findings altogether indicate that allogeneic ADSCs suppress inflammation and improve the secretory function of salivary glands in an IL-33-dependent manner. To understand the underlying mechanisms by which allogeneic ADSCs IL-33 suppressed inflammation and improved the function of submandibular glands, we examined the changes of Tregs and proinflammatory effector cells in the submandibular glands of NOD mice. Strikingly, WT ADSCs treatment resulted in a significant increase in both the frequency and absolute number of CD4+Foxp3+ Tregs in the submandibular glands in SS-like NOD mice compared with other groups (Figure 5A). More importantly, WT ADSCs treatment, but not Il33−/− ADSCs treatment, led to a significant increase in the frequency and total number of ST2+ Tregs (Figure 5B). Further analysis of in vivo Treg expansion with Ki67 staining revealed that WT ADSCs treatment caused significantly more Ki67+ Tregs in the submandibular glands than did Il33−/− ADSCs or PBS treatment, suggesting IL-33-driven Treg proliferation upon WT ADSCs transplantation (Figure 5C). As IL-33 is also associated with the differentiation and function of various lymphocytes including type 2 helper T (Th2) cells and ILC2s (Licona-Limon et al., 2013Licona-Limon P. Kim L.K. Palm N.W. Flavell R.A. TH2, allergy and group 2 innate lymphoid cells.Nat. Immunol. 2013; 14: 536-542Crossref PubMed Scopus (446) Google Scholar; Molofsky et al., 2013Molofsky A.B. Nussbaum J.C. Liang H.E. Van Dyken S.J. Cheng L.E. Mohapatra A. Chawla A. Locksley R.M. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages.J. Exp. Med. 2013; 210: 535-549Crossref PubMed Scopus (548) Google Scholar; Moro et al., 2010Moro K. Yamada T. Tanabe M. Takeuchi T. Ikawa T. Kawamoto H. Furusawa J. Ohtani M. Fujii H. Koyasu S. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells.Nature. 2010; 463: 540-544Crossref PubMed Scopus (1364) Google Scholar; Schmitz et al., 2005Schmitz J. Owyang A. Oldham E. Song Y. Murphy E. McClanahan T.K. Zurawski G. Moshrefi M. Qin J. Li X. et al.IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines.Immunity. 2005; 23: 479-490Abstract Full Text Full Text PDF PubMed Scopus (2604) Google Scholar) in addition to Tregs, we studied Th2 (IL-4+, IL-13+) CD4+ T cells and ILC2s in the submandibular glands among all the groups of NOD mice and no significant differences could be observed (Figures S4–S7). Furthermore, the frequency of IL-13-expressing (Lin−CD45+GATA3+ST2+IL-13+) and IL-4-producing (Lin−CD45+GATA3+ST2+IL-4+) ILC2 subsets also did not exhibit changes after ADSCs treatment (Figures S8A–S8C). Interestingly, the frequency of CD8+TCRαβ+IL-4+ T cells increased in the submandibular glands of WT ADSCs-treated group compared with Il33−/− ADSCs- or PBS-treated groups (Figure S6D), but the significance of the increase remains unknown. We next examined the CD45+ inflammatory cells in the submandibular glands. WT ADSCs treatment caused significantly fewer CD45+ cells in the submandibular glands than Il33−/− ADSCs or PBS-treated mice (Figure 5D). The absolute number of CD4+ (Figure 5E) and CD8+ (Figure 5F) T cells, but not TCRγδ+ T cells (Figure 5G), significantly decreased in WT ADSC-treated mice compared with IIl33−/− ADSCs- or PBS- treated groups. Consequently, the total number of IFN-γ+CD4+ T cells (Th1) and IFN-γ+CD8+ T cells were decreased in WT ADSC-treated NOD mice, although the frequency did not change significantly (Figures S4B–S4E, S5A, S5E, S6A, S6E, S7A, and S7E). Interestingly, both WT and Il33−/− mADSCs treatment showed a similar reduction of IL-17+ T cells compared with the PBS group, suggesting that the decrease of IL-17 was independent of IL-33 (Figures S5B and S7B). In contrast to the submandibular glands, there was no significant difference in the frequency and number of CD4+Foxp3+ Tregs, ST2+Tregs and Ki67+ Tregs in the spleen, and armpit, inguinal and submandibular lymph nodes of all groups of NOD/ShiLtj mice (Figure S9). Taken together, these data indicate that mADSCs-IL-33-mediated suppression of inflammation and improvement of submandibular gland function was mainly ascribed to the enhanced number of ST2+ Tregs and reduced the number of CD45+ proinflammatory cells especially IFN-γ+ T cells in the glands. We next investigated whether human ADSCs also expressed IL-33 and IL-1β upregulated its expression. For this, we cultured human ADSCs with or without 2 ng/mL IL-1β for 6 and 24 h and then checked IL33 mRNA and IL-33 protein, respectively. Untreated human ADSCs hardly exhibited IL-33; however, IL-1β treatment significantly upregulated the amount of IL33 mRNA in human ADSCs at 6 h (Figure 6A). IL-33 protein was also increased significantly by IL-1β treatment in human ADSCs at 24 h (Figure 6B). We also studied the signal pathways for IL-33 production by human ADSCs in response to IL-1β. Consistent with murine ADSCs, the levels of phosphorylated ERK and p38 proteins were significantly increased in human ADSCs after IL-1β stimulation compared with the unstimulated cells (Figure 6C). Moreover, the selective protein kinase inhibitors (5Z)-7-oxozeaenol, U0126, and SB203580, which inhibit TAK1, ERK, and p38 MAPK, respectively, significantly decreased the inductive effect of IL-1β on IL33 mRNA and IL-33 protein in human ADSCs (Figures 6D and 6E). TAK1 inhibitor also decreased the relative ratio of phosphorylated ERK/ERK and phosphorylated p38/p38 (Figure 6F). These data indicated that human ADSCs also produce IL-33 by IL-1β stimulation through TAK1-ERK/p38 signal pathways, suggesting a translational relevance and significance" @default.
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• W3154606485 date "2021-05-01" @default.
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• W3154606485 title "Adipose-mesenchymal stromal cells suppress experimental Sjögren syndrome by IL-33-driven expansion of ST2+ regulatory T cells" @default.
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• W3154606485 doi "https://doi.org/10.1016/j.isci.2021.102446" @default.
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