Biology subjects

Franco, J. M.

Publications and source records attributed to Franco, J. M..

2 recordsLinked to original sources

bioRxiv2023

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

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.

cell biology↗

bioRxiv2023

MAPK/MAK/MRK overlapping kinase (MOK) controls microglial inflammatory/type-I IFN responses via Brd4 and is involved in ALS pathophysiology

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease affecting motor neurons and characterized by microglia-mediated neurotoxic inflammation whose underlying mechanisms remain incompletely understood. In this work we reveal that MAPK/MAK/MRK overlapping kinase (MOK), with unknown physiological substrate, displays an immune function by controlling inflammatory and type-I IFN responses in microglia which are detrimental to primary motor neurons. Moreover, we uncover the epigenetic reader bromodomain-containing protein 4 (Brd4) as the first molecule regulated by MOK, by promoting Ser492-phospho-Brd4 levels. We further demonstrate that MOK regulates Brd4 functions by supporting its binding to cytokine gene promoters, therefore enabling innate immune responses. Remarkably, we show that MOK levels are increased in ALS spinal cord, particularly in microglial cells, and that administration of a chemical MOK-inhibitor to ALS model mice is able to modulate Ser492-phospho-Brd4 levels, suppress microglial activation and modify disease course, indicating a pathophysiological role of MOK kinase in ALS and neuroinflammation.

neuroscience↗