PXD045222

PXD045222 is an original dataset announced via ProteomeXchange.

Title	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
Description	The intricate aetiology of type 1 diabetes mellitus (T1DM) implicating a detrimental cross talk between immune cells and insulin producing -cells leading to their destruction has stumped the development of effective disease modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can revert hyperglycemia in pre-clinical mouse models of T1DM by attenuating the autoimmune attack coupled to -cell survival/regeneration, prompt us to investigate whether LRH-1/NR5A2-mediated immune tolerization could be achieved in individuals with 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-derived macrophages (MDM1) and mature dendritic cells (mDCs) from individuals with T1DM. Mechanistically, mitohormesis was induced in MDM1 restricting pro-inflammation propagation while mitochondria turnover was increased in mDCs assisting transit towards a tolerogenic phenotype. BL001 treatment also increased T-regulatory cells within the T-cell subpopulation. BL001-treated MDM1, mDCs or T-cells impeded T-effector cell expansion. Engraftment and function of human islets transplanted into hyperglycemic immunocompetent mice was enhanced by BL001 treatment leading to improved glycemia. Collectively, LRH-1/NR5A2 agonism fosters a coordinated re-programming of T1DM immune cells from a pro- to an anti-inflammatory/tolerizing phenotype empowering them to repress cytotoxic T-cell proliferation and facilitates islet engraftment and function after transplantation. Our finding demonstrate the feasibility of re-establishing human immune tolerance within a pro-inflammatory environment, rather than suppression, opening an unprecedent pharmacological therapeutic venue for T1DM.
HostingRepository	PRIDE
AnnounceDate	2025-04-09
AnnouncementXML	Submission_2025-04-09_14:17:09.277.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Román González-Prieto
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-08 05:30:34	ID requested
⏵ 1	2025-04-09 14:17:09	announced

10.1002/CTM2.70134;

submitter keyword: Type 1 Diabetes Mellitus

Román González-Prieto
contact affiliation	CABIMER
contact email	roman.gonzalez@cabimer.es
lab head
Román González-Prieto
contact affiliation	Andalusian Center for Regenerative Medicine and Cell Biology, CABIMER, University of Seville
contact email	roman.gonzalez@cabimer.es
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/04/PXD045222

PRIDE project URI

• PRIDE
  1. PXD045222
     1. Label: PRIDE project
     2. Name: 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