Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression

Autor(es):Mostrar menos -

Polonio, Carolina Manganeli ^[1] ; de Freitas, Carla Longo ^[1] ; de Oliveira, Marilia Garcia ^[1] ; Rossato, Cristiano ^[1] ; Brandao, Wesley Nogueira ^[1] ; Zanluqui, Nagela Ghabdan ^{[1, 2]} ; de Oliveira, Lilian Gomes ^[1] ; Nishiyama Mimura, Luiza Ayumi ^[3] ; Barros Silva, Maysa Braga ^[4] ; Garcia Calich, Vera Lucia ^[5] ; Nisenbaum, Marcelo Gil ^[6] ; Halpern, Silvio ^[7] ; Evangelista, Lucila ^[6] ; Maluf, Mariangela ^[8] ; Perin, Paulo ^[8] ; Czeresnia, Carlos Eduardo ^[6] ; Schatzmann Peron, Jean Pierre ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Immunol, Neuroimmune Interact Lab, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Sch Med, Immunopathol & Allergy Post Grad Program, Sao Paulo, SP - Brazil

^[3] UNESP, Inst Biosci, Botucatu, SP - Brazil

^[4] Univ Sao Paulo, Clin Anal Dept, Clin Biochem Lab, Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, SP - Brazil

^[6] Celula Mater, Div Reprod Med, Sao Paulo, SP - Brazil

^[7] Halpern Clin, Div Reprod Med, Sao Paulo, SP - Brazil

^[8] CEERH, Div Reprod Med, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Clinical Science; v. 135, n. 9, p. 1065-1082, MAY 2021.
• Citações Web of Science: 0

Resumo

Cellular therapy with mesenchymal stem cells (MSCs) is a huge challenge for scientists, as little translational relevance has been achieved. However, many studies using MSCs have proved their suppressive and regenerative capacity. Thus, there is still a need for a better understanding of MSCs biology and the establishment of newer protocols, or to test unexplored tissue sources. Here, we demonstrate that murine endometrial-derived MSCs (meMSCs) suppress Experimental Autoimmune Encephalomyelitis (EAE). MSC-treated animals had milder disease, with a significant reduction in Th1 and Th17 lymphocytes in the lymph nodes and in the central nervous system (CNS). This was associated with increased Il27 and Cyp1a1 expression, and presence of IL-10-secreting T CD4(+) cells. At EAE peak, animals had reduced CNS infiltrating cells, histopathology and demyelination. qPCR analysis evidenced the down-regulation of several pro-inflammatory genes and up-regulation of indoleamine-2,3-dioxygenase (IDO). Consistently, co-culturing of WT and IDO-/- meM-SCs with T CD4(+) cells evidenced the necessity of IDO on the suppression of encephalitogenic lymphocytes, and IDO-/- meMSCs were not able to suppress EAE. In addition, WT meMSCs stimulated with IL-17A and IFN-gamma increased IDO expression and secretion of kynurenines in vitro, indicating a negative feedback loop. Pathogenic cytokines were in-creased when CD4(+) T cells from AhR(-/-) mice were co-cultured with WT meMSC. In sum-mary, our research evidences the suppressive activity of the unexplored meMSCs popula-tion, and shows the mechanism depends on IDO-kynurenines-Aryl hydrocarbon receptor (AhR) axis. To our knowledge this is the first report evidencing that the therapeutic potential of meMSCs relying on IDO expression. (AU)

• Processo FAPESP: 18/10242-5 - Papel do receptor ionotrópico de glutamato NMDA em células da imunidade inata e adaptativa da mucosa intestinal em modelo experimental murino
• Beneficiário: Marília Garcia de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/22504-1 - O papel dos receptores TAM e seus ligantes, Gas6 e Pros1, na Síndrome Congênita do Zika Vírus Experimental
• Beneficiário: Jean Pierre Schatzmann Peron
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/11828-0 - Avaliação do papel dos microRNAs na imunopatogênese da microcefalia causada pelo Zika vírus em modelos experimentais
• Beneficiário: Carolina Manganeli Polonio
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/07371-2 - Caracterização do papel de linfócitos T CD8+ na infecção por Zika vírus
• Beneficiário: Nagela Ghabdan Zanluqui
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/26170-0 - Neuroimunobiologia em modelo experimental de Encefalomielite Autoimune e Síndrome Congênita do Zika Vírus: fisiopatogenia, susceptibilidade, terapia celular, vacinação
• Beneficiário: Carolina Demarchi Munhoz
• Modalidade de apoio: Auxílio à Pesquisa - Temático