Immunometabolic reprogramming by LRH-1/NR5A2 pharmacological activation resolves inflammation in immune cells of type 1 diabetes mellitus individuals and improves human islet engraftment and function

Cobo-vuilleumier, N.; Rodriguez-Fernandez, S.; Lopez-Noriega, L.; Lorenzo, P. I.; Franco, J. M.; Lachaud, c. C.; Martin-Vazquez, E.; Araujo Legido, R.; Dorronsoro, A.; Lopez-Fernandez-Sobrino, R.; Salas-Lloret, D.; van Overbeek, N.; Ramos-Rodriguez, M.; Mateo-Rodriguez, C.; Hidalgo, L.; Nano, R.; Arroba, A. I.; Campos Caro, A.; Vertegaal, A. C.; Martin Montalvo, A.; Martin, F.; Aguilar-Diosdado, M.; Piemonti, L.; Pasquali, L.; Gonzalez Prieto, R.; Garcia Sanchez, M. I.; Martinez-Brocca, M.; Vives-Pi, M.; Gauthier, B. R.

doi:10.1101/2023.09.18.558230

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bioRxiv · 10.1101/2023.09.18.558230

Immunometabolic reprogramming by LRH-1/NR5A2 pharmacological activation resolves inflammation in immune cells of type 1 diabetes mellitus individuals and improves human islet engraftment and function

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Abstract

The intricate etiology of type 1 diabetes mellitus (T1D), marked by a detrimental cross-talk between the immune system and insulin-producing {beta}-cells, has impeded effective disease-modifying therapies. The discovery that pharmacological activation of the nuclear receptor LRH-1/NR5A2 can reverse hyperglycemia in mouse models of T1D by attenuating the autoimmune attack coupled to {beta}-cell survival/regeneration, prompted us to investigate whether immune tolerization could be achieved in individuals with T1D by LRH-1/NR5A2 activation as well as improving islet function/survival after xenotransplantation in mice. Pharmacological activation of LRH-1/NR5A2 induced a coordinated genetic and metabolic reprogramming of T1D macrophages and dendritic cells, shifting them from a pro-to an anti-inflammatory/tolerogenic phenotype. Regulatory T-cells were also expanded resulting in the impediment of cytotoxic T-cell proliferation. LRH-1/NR5A2 activation enhanced human islet engraftment and function in hyperglycemic immunocompetent mice. In summary our findings demonstrate the feasibility of re-establishing immune tolerance within a pro-inflammatory environment, opening a new therapeutic venue for T1D.

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Cobo-vuilleumier, N., Rodriguez-Fernandez, S., Lopez-Noriega, L., Lorenzo, P. I., Franco, J. M., Lachaud, c. C., Martin-Vazquez, E., Araujo Legido, R., Dorronsoro, A., Lopez-Fernandez-Sobrino, R., Salas-Lloret, D., van Overbeek, N., Ramos-Rodriguez, M., Mateo-Rodriguez, C., Hidalgo, L., Nano, R., Arroba, A. I., Campos Caro, A., Vertegaal, A. C., Martin Montalvo, A., Martin, F., Aguilar-Diosdado, M., Piemonti, L., Pasquali, L., Gonzalez Prieto, R., Garcia Sanchez, M. I., Martinez-Brocca, M., Vives-Pi, M., Gauthier, B. R.. 2023-09-18. Immunometabolic reprogramming by LRH-1/NR5A2 pharmacological activation resolves inflammation in immune cells of type 1 diabetes mellitus individuals and improves human islet engraftment and function. https://doi.org/10.1101/2023.09.18.558230

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