In innate immune responses, induction of type-I interferons (IFNs) prevents virus spreading while viral replication is delayed by protein synthesis inhibition. We asked how cells perform these apparently contradictory activities. Using single fibroblast monitoring by flow cytometry and mathematical modeling, we demonstrate that type-I IFN production is linked to cell's ability to enter dsRNA-activated PKR-dependent translational arrest and then overcome this inhibition by decreasing eIF2a phosphorylation through phosphatase 1c cofactor GADD34 (Ppp1r15a) expression. GADD34 expression, shown here to be dependent on the IRF3 transcription factor, is responsible for a biochemical cycle permitting pulse of IFN synthesis to occur in cells undergoing protein synthesis inhibition. Translation arrest is further demonstrated to be key for anti-viral response by acting synergistically with MAVS activation to amplify TBK1 signaling and IFN-b mRNA transcription, while GADD34-dependent protein synthesis recovery contributes to the heterogeneous expression of IFN observed in dsRNA-activated cells.

Immune cells detect specific microbes or damage to tissue integrity in order to initiate efficient immune responses. Abnormal accumulation of proteins in the endoplasmic reticulum (ER) can be seen as a sign of cellular malfunction and stress that triggers a collection of conserved emergency rescue programs. These different signaling cascades, which favor ER proteostasis and promote cell survival, are collectively known as the unfolded protein response (UPR). In recent years, a synergy between the UPR and inflammatory cytokine production has been unraveled, with different branches of the UPR entering in a cross‐talk with specialized microbe sensing pathways, which turns on or amplify inflammatory cytokines production. Complementary to this synergetic activity, UPR induction alone, can itself be seen as a danger signal, and triggers directly or indirectly inflammation in different cellular and pathological models, this independently of the presence of pathogens. Here, we discuss recent advances on the nature of these cross‐talks and how innate immunity, metabolism dysregulation, and ER‐signaling pathways intersect in specialized immune cells, such as dendritic cells (DCs), and contribute to the pathogenesis of inflammatory diseases.