Premium
Deletion of delta‐like 1 homologue accelerates renal inflammation by modulating the Th17 immune response
Author(s) -
MarquezExposito Laura,
RodriguesDiez Raul R.,
RayegoMateos Sandra,
FierroFernandez Marta,
RodriguesDiez Raquel,
Orejudo Macarena,
SantosSanchez Laura,
Blanco Eva Maria,
Laborda Jorge,
Mezzano Sergio,
Lamas Santiago,
Lavoz Carolina,
RuizOrtega Marta
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201903131r
Subject(s) - inflammation , immune system , immunology , cancer research , medicine
Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta‐like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1 ‐null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey‐1 expression compared to wild‐type (WT) littermates. NOTCH1 over‐activation in Dlk1 ‐null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL‐17A and other related‐inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non‐canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17‐mediated inflammatory response.