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.