At the crossway of ER‐stress and proinflammatory responses

Abstract

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.

Elevation of the unfolded protein response increases RANKL expression

“…We also noted that Tm increased apoptosis in these cultures as measured by caspase‐3 activity after 12 hours, (Figure B). The latter finding is consistent with prior evidence that cytokine production and cell death are often consequences of prolonged UPR, especially with agents like Tm …”

“…Accumulation of misfolded proteins results in ER stress leading to activation of the unfolded protein response (UPR) that restores proteostasis by stimulating ERAD and increasing protein folding capacity . Chronic or unresolved ER stress initiates proapoptotic signaling as well as increased production of inflammatory cytokines like TNF‐α, IL ‐6, interferon‐γ, and other factors such as vascular endothelial growth factor (VEGF), that are involved in tissue repair …”

NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production

“…Obesity elicits ER stress coupled with inflammation in liver and adipose tissue. ER stress plays a key role in the development of hepatic IR and steatosis . Adipose trNK cells and group 1 innate lymphoid cells (ILC1) are responsible for the development of obesity‐associated IR and inflammation .…”

“…Obesity drives a low‐grade and chronic systemic inflammation, which stems primarily from a dysregulated immune system . Inflammation has a close cross‐talk between ER stress and IR . ER stress is coupled with inflammation in health and disease.…”

“…ER stress is coupled with inflammation in health and disease. Proinflammatory cytokines, such as TNF‐α, IL‐1β, and IL‐6 induce ER stress and IR in hepatocytes, which further disrupt metabolic responses and cause more inflammation . Secreted osteopontin (OPN) is a matrix glycoprotein and proinflammatory cytokine.…”