LRH-1/NR5A2 Activation Rewires Immunometabolism Blunting Inflammatory Immune Cell Progression in Individuals with Type 1 Diabetes and Enhances Human Islet Function in Mice

ABSTRACT The intricate etiology of type 1 diabetes mellitus (T1D), marked by a detrimental cross-talk between the immune system and insulin-producing β-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 β-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.