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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

Abstract : Signaling through the mechanistic target of rapamycin complex 1 (mTORC1) is a major regulatory node of pro-inflammatory mediator production by macrophages (MΦs). 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 MΦs 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 MΦs 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 MΦs 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 MΦs.
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https://hal-riip.archives-ouvertes.fr/pasteur-02275488
Contributor : Michel Courcelles <>
Submitted on : Friday, August 30, 2019 - 6:29:11 PM
Last modification on : Monday, September 2, 2019 - 11:50:45 AM

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Mirtha William, Louis-Philippe Leroux, Visnu Chaparro, Tyson Graber, Tommy Alain, et al.. 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, Wiley-VCH Verlag, 2019, 49 (8), pp.1200-1212. ⟨10.1002/eji.201847857⟩. ⟨pasteur-02275488⟩

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