DDIT4L regulates mitochondrial and innate immune activities in early life
Christina Michalski, Claire Cheung, Ju Hee Oh, Emma Ackermann, Constantin R. Popescu, Anne-Sophie Archambault, Martin A. Prusinkiewicz, Rachel Da Silva, Abdelilah Majdoubi, Marina Viñeta Paramo, Rui Yang Xu, Frederic Reicherz, Annette E. Patterson, Liam Golding, Ashish A. Sharma, Chinten J. Lim, Paul C. Orban, Ramon I. Klein Geltink, Pascal M. Lavoie
Christina Michalski, Claire Cheung, Ju Hee Oh, Emma Ackermann, Constantin R. Popescu, Anne-Sophie Archambault, Martin A. Prusinkiewicz, Rachel Da Silva, Abdelilah Majdoubi, Marina Viñeta Paramo, Rui Yang Xu, Frederic Reicherz, Annette E. Patterson, Liam Golding, Ashish A. Sharma, Chinten J. Lim, Paul C. Orban, Ramon I. Klein Geltink, Pascal M. Lavoie
View: Text | PDF
Research Article Immunology

DDIT4L regulates mitochondrial and innate immune activities in early life

Abstract

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.

Authors

Christina Michalski, Claire Cheung, Ju Hee Oh, Emma Ackermann, Constantin R. Popescu, Anne-Sophie Archambault, Martin A. Prusinkiewicz, Rachel Da Silva, Abdelilah Majdoubi, Marina Viñeta Paramo, Rui Yang Xu, Frederic Reicherz, Annette E. Patterson, Liam Golding, Ashish A. Sharma, Chinten J. Lim, Paul C. Orban, Ramon I. Klein Geltink, Pascal M. Lavoie

×

Figure 5

Low DDIT4L gene expression is linked to severe bronchopulmonary dysplasia in preterm neonates during the neonatal period.

Options: View larger image (or click on image) Download as PowerPoint
Low DDIT4L gene expression is linked to severe bronchopulmonary dysplasi...
(A) DDIT4L expression in lung macrophages over a range of postnatal days, between neonates with no BPD or those with mild, moderate, or severe BPD. Data were obtained from GEO accession GSE149490 and included 4–25 infants per bronchopulmonary dysplasia [BPD] severity group, but the same number of samples were not necessarily available for all time points, as samples were collected only in infants that were endotracheally intubated for ventilation. Significant differences in DDIT4L gene expression are shown at postnatal day 7 and 14 (at the time when early BPD clinical signs usually develop; severity groups were compared at each postnatal day using a 2-sided unpaired t test with Welch’s correction for unequal variance; *P < 0.05). (B) Expression heatmap of cytokine and chemokine genes (same data set) on postnatal day 7 (1–14 infants per BPD severity group) showing decreased proinflammatory cytokine and chemokines and increased antiinflammatory cytokine gene expression with increasing DDIT4L gene expression (*statistically significant at FDR 5%). Additionally, see Supplemental Table 3 for pathways correlating with DDIT4L gene expression.