Título : Activation of the Immunoregulatory Cation Channel TMEM176B by a Nitroalkene Derivative of Salicylate Prolongs Graft Survival
Autor(es) : Galliussi, Germán
Noboa, Javier
Leyva, Alejandro
Russo, Sofía
Collela, Lucía
Usal, Claire
Malcuori, Mateo
Charbonnier, David
Escande, Carlos
López, Gloria Virginia
Durán, Rosario
Anegón, Ignacio
Hill, Marcelo
Batthyány, Carlos
Segovia, Mercedes
Fecha de publicación : 22-jul-2025
Tipo de publicación: Artículo
Versión: Publicado
Publicado por: Wolters Kluwer Health, Inc
Publicado en: Transplantation
Areas del conocimiento : Ciencias Médicas y de la Salud
Medicina Básica
Inmunología
Otros descriptores : TMEM176B
Heme oxygenase-1
Nitroalkenes
Allograft
Resumen : Background. Targeting emerging immunoregulatory molecules may open new therapeutic perspectives to control alloresponses and alleviate the burden of immunosuppressors. Transmembrane protein 176B (TMEM176B) is an intracellular cation channel highly expressed by myeloid cells. We have shown that TMEM176B is associated with allograft tolerance. Moreover, it controls the tolerogenic function of dendritic cells and inhibits NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome. Here, we speculated that pharmacological activation of TMEM176B by the nitroalkene derivative of 5-(2-nitroethenyl) salicylic acid (SANA) may prolong allograft survival through active immunoregulatory mechanisms. Methods. SANA impact on TMEM176B activity was studied in vitro and in vivo. We assessed the potential efficacy of SANA treatment in prolonging graft survival in 2 allograft models: a mouse skin model with minor mismatches and a rat heart model with fully mismatches. Wild type and Tmem176b−/− recipient mice were used. Graft survival and innate and adaptive immune response were analyzed at the skin graft and draining lymph nodes through flow cytometry studies. Results. SANA was identified as an activator of TMEM176B-dependent ion transport. SANA prolongs allograft survival in a Tmem176b-dependent manner. SANA triggered the expression of the immunoregulatory enzyme heme oxygenase-1 in wild type but not in Tmem176b−/− MHCII+CD11chighCD11b+ conventional dendritic cells within the graft. SANA therapy was associated with increased CD4+Forkhead box P3+ regulatory T (Treg) in the graft. The heme oxygenase-1 inhibitor tin protoporphyrin IX completely blocked the effect of SANA on graft survival and Treg in vivo. Furthermore, Treg modulation by anti-CD3 antibodies improves the graft-protecting effect of SANA. Conclusions. SANA-mediated activation of TMEM176B triggers an immunoregulatory pathway that prolongs skin and heart graft survival.
URI / Handle: https://hdl.handle.net/20.500.12381/5227
DOI: 10.1097/TP.0000000000005483
Institución responsable del proyecto: Institut Pasteur de Montevideo
Institut National de la Sante et la Recherche Medicale (INSERM), Centre de Recherche en Transplantation et Immunologie UMR1064
Universidad de la República
Financiadores: MERCOSUR Structural Convergence Fund (FOCEM) Convenio de Financiamiento (COF) 03/11
Agencia Nacional de Investigación e Innovación
Comisión Académica de Posgrado, Universidad de la República
Identificador ANII: POS_NAC_2018_1_151162
Nivel de Acceso: Acceso restringido
Aparece en las colecciones: Institut Pasteur de Montevideo

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