William, Mirtha; Leroux, Louis-Phillipe; Chaparro, Visnu; Graber, Tyson; Alain, Tommy et Jaramillo, Maritza 
ORCID: https://orcid.org/0000-0002-1910-5684
(2019).
Translational repression of Ccl5 and Cxcl10 by 4E-BP1 and 4E-BP2 restrains the ability of mouse macrophages to induce migration of activated T cells
European Journal of Immunology
, vol. 49
, nº 8.
pp. 1200-1212.
DOI: 10.1002/eji.201847857.
Résumé
Signaling through the mechanistic target of rapamycin complex 1 (mTORC1) is a major regulatory node of pro-inflammatory mediator production by macrophages (MPhis). However, it is still unclear whether such regulation relies on selective translational control by two of the main mTORC1 effectors, the eIF4E-binding proteins 1 and 2 (4E-BP1/2). By comparing translational efficiencies of immune-related transcripts of MPhis from WT and 4E-BP1/2 double-KO (DKO) mice, we found that translation of mRNAs encoding the pro-inflammatory chemokines CCL5 and CXCL10 is controlled by 4E-BP1/2. Macrophages deficient in 4E-BP1/2 produced higher levels of CCL5 and CXCL10 upon LPS stimulation, which enhanced chemoattraction of activated T cells. Consistent with this, treatment of WT cells with mTORC1 inhibitors promoted the activation of 4E-BP1/2 and reduced CCL5 and CXCL10 secretion. In contrast, the phosphorylation status of eIF4E did not affect the synthesis of these chemokines since MPhis derived from mice harboring a non-phosphorylatable form of the protein produced similar levels of CCL5 and CXCL10 to WT counterparts. These data provide evidence that the mTORC1-4E-BP1/2 axis contributes to regulate the production of chemoattractants by MPhis by limiting translation efficiency of Ccl5 and Cxcl10 mRNAs, and suggest that 4E-BP1/2 act as immunological safeguards by fine-tuning inflammatory responses in MPhis.
| Type de document: | Article |
|---|---|
| Mots-clés libres: | 4E-BP; chemokines; mRNA translation; mTOR; macrophages |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 11 janv. 2020 15:40 |
| Dernière modification: | 15 févr. 2022 18:17 |
| URI: | https://espace.inrs.ca/id/eprint/8600 |
Gestion Actions (Identification requise)
 |
Modifier la notice |