LRH-1/NR5A2 Activation in Immune Cells from Individuals with Type 1 Diabetes Mellitus Mitigates Inflammation via Immunometabolic Reprogramming and Enhanced Human Islet Function in Mice

Abstract

SUMMARYThe intricate etiology of type 1 diabetes mellitus (T1DM), 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 T1DM by attenuating the autoimmune attack coupled to β-cell survival/regeneration, prompted us to investigate whether immune tolerization could be achieved in individuals with T1DM 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 immunometabolic reprogramming of T1DM 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. These findings demonstrate the feasibility of re-establishing immune tolerance within a pro-inflammatory environment, opening a new therapeutic venue for T1DM.