DDIT4L regulates mitochondrial and innate immune activities in early life.

Autor: Michalski C; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pediatrics and., Cheung C; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pediatrics and., Oh JH; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Ackermann E; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada., Popescu CR; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pediatrics and.; Department of Pediatrics, Université Laval, Quebec, Quebec, Canada., Archambault AS; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Prusinkiewicz MA; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pediatrics and., Da Silva R; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada., Majdoubi A; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pediatrics and., Viñeta Paramo M; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Women+ and Children's Health, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada., Xu RY; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Women+ and Children's Health, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada., Reicherz F; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pediatrics and., Patterson AE; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Golding L; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pediatrics and.; Women+ and Children's Health, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada., Sharma AA; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA., Lim CJ; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pediatrics and., Orban PC; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada., Klein Geltink RI; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Lavoie PM; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Pediatrics and.; Women+ and Children's Health, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2024 Feb 06; Vol. 9 (5). Date of Electronic Publication: 2024 Feb 06.
DOI: 10.1172/jci.insight.172312
Abstrakt: Pattern recognition receptor responses are profoundly attenuated before the third trimester of gestation in the relatively low-oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics, and innate immune activity. Using genetically engineered monocytic U937 cells, we confirmed that DDIT4L overexpression altered mitochondrial dynamics, suppressing their activity, and blunted LPS-induced cytokine responses. We also showed that monocyte mitochondrial function is more restrictive in earlier gestation, resembling the phenotype of DDIT4L-overexpressing U937 cells. Gene expression analyses in neonatal granulocytes and lung macrophages in preterm infants confirmed upregulation of the DDIT4L gene in the early postnatal period and also suggested a potential protective role against inflammation-associated chronic neonatal lung disease. Taken together, these data show that DDIT4L regulates mitochondrial activity and provide what we believe to be the first direct evidence for its potential role supressing innate immune activity in myeloid cells during development.
Databáze: MEDLINE