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.

Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors

“…A number of prior studies showed the requirement of mTOR for chemokine induction in some immune cell subsets, such as monocytes and macrophages (Jin and Zhao, 2020;Lin et al, 2014;William et al, 2019). Therefore, we investigated whether mTOR was similarly involved in chemokine induction in breast cancer cells treated with CDK4/6i.…”

Impact of Interleukin 10 Deficiency on Intestinal Epithelium Responses to Inflammatory Signals

“…This is because there are clear limitations of the enteroid model which do not represent the complex interplay for immune and stromal cells that would be found in vivo . Also, it is known that Cxcl10 transcription depends on protein synthesis ( 86 , 87 ) and on additional transcription factors, such as activator protein 1 (AP-1) ( 87 ) and key transcriptional repressors 4E-BP1/2 ( 88 ).…”

Translational profiling of macrophages infected with Leishmania donovani identifies mTOR- and eIF4A-sensitive immune-related transcripts

“…Among post-transcriptional mechanisms, transcript-selective changes in translational efficiencies enable cells to swiftly remodel their proteomes in response to environmental cues without requiring de novo mRNA synthesis [10][11][12][13]. In eukaryotes, translational efficiency is mainly regulated at the initiation step when ribosomes are recruited to the mRNA [14].…”