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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

William, Mirtha; Leroux, Louis-Phillipe; Chaparro, Visnu; Graber, Tyson; Alain, Tommy; Jaramillo, Maritza (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. p. 1200-1212. DOI: 10.1002/eji.201847857.

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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: 11 janv. 2020 15:40
URI: http://espace.inrs.ca/id/eprint/8600

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