Pharmacological activation of LRH-1/NR5A2 triggers an anti-inflammatory phenotypic switch in immune cells from individuals with type 1 diabetes and improves human islet engraftment/function

The intricate aetiology of type 1 diabetes mellitus (T1DM) implicating a detrimentalcross talk between immune cells and insulin producing beta-cells leading to theirdestruction has stumped the development of effective disease modifying therapies.The discovery that the pharmacological activation of LRH-1/NR5A2 can reverthyperglycemia in pre-clinical mouse models of T1DM by attenuating the autoimmuneattack coupled to inducing beta-cell survival/regeneration, prompt us to investigatewhether LRH-1/NR5A2-mediated immune tolerization could be achieved in individualswith T1DM and improve islet survival and function subsequent to xenotransplantation.We found that LRH-1/NR5A2 activation using the agonist BL001 blunted the pro-inflammatory genetic signature and cytokine secretome of both monocyte-derivedmacrophages (MDM1) and mature dendritic cells (mDCs) from individuals with T1DM.Mechanistically, mitohormesis was induced in MDM1 restricting pro-inflammationpropagation while mitochondria turnover was increased in mDCs assisting transittowards a tolerogenic phenotype. BL001 treatment also increased T-regulatory cellswithin the T-cell subpopulation. BL001-treated MDM1, mDCs or T-cells impeded T-effector cell expansion. Engraftment and function of human islets transplanted intohyperglycemic immunocompetent mice was enhanced by BL001 treatment leading toimproved glycemia. Collectively, LRH-1/NR5A2 agonism fosters a coordinated re-programming of T1DM immune cells from a pro- to an anti-inflammatory/tolerizingphenotype empowering them to repress cytotoxic T-cell proliferation and facilitates isletengraftment and function after transplantation. Our findings demonstrate the feasibilityof re-establishing human immune tolerance within a pro-inflammatory environment,rather than suppression, opening an unprecedent pharmacological therapeutic venuefor T1DM.