ATF6 Mediates a Pro-Inflammatory Synergy Between ER Stress and TLR Activation in the Pathogenesis of Liver Ischemia-Reperfusion Injury

Abstract

Although roles of the metabolic stress in organ ischemia reperfusion injury (IRI) have been well recognized, the question of whether and how these stress responses regulate innate immune activation against IR remains unclear. In a murine liver partial warm ischemia mode, we showed that prolonged ischemia triggered endoplasmic reticulum (ER) stress response, particularly, the ATF6 branch, in liver Kupffer cells and altered their responsiveness against TLR stimulation. Ischemia-primed cells increased pro-, but decreased anti-, inflammatory cytokine productions. Alleviation of ER stress in vivo by small chemical chaperon 4-phenylbutyrate or ATF6 siRNA diminished the pro-inflammatory priming effect of ischemia in KCs, leading to the inhibition of liver immune response against IR and protection of livers from IRI. In vitro, ATF6 siRNA abrogated the ER stress-mediated pro-inflammatory enhancement of macrophage TLR4 response, by restricting NF-kB and restoring Akt activations. Thus, ischemia primes liver innate immune cells by ATF6-mediated ER stress response. The IR-induced metabolic stress and TLR activation function in synergy to activate tissue inflammatory immune response.

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

“…Loss of either IRE1α or PERK reduces NF-κB during ER stress, indicating a synergistic effect of these kinases on NF-κB activity (Tam et al 2012). In addition, two studies have shown that ATF6 stimulates NF-κB activity downstream of AKT phosphorylation (Yamazaki et al 2009, Rao et al 2014.…”

Hyperglycemia and Liver Ischemia Reperfusion Injury: A Role for the Advanced Glycation Endproduct and Its Receptor Pathway

“…The efficacy of RAGE knock-down by the siRNA was confirmed in vitro in macrophages (by Western blots, Figure 5A). Administration of RAGE siRNA carried by phagocyte-targeting mannose-conjugated polymers (27) in diabetic mice prior to the start of liver ischemia resulted in significant inhibition of RAGE expression in livers (qRT-PCR) ( Figure 5B), leading to the protection of livers from IRI (sALT and histology with Suzuki scores) and inhibition of neutrophil activation (MPO activities) ( Figure 5C-E). Liver pro-inflammatory gene induction was also inhibited by RAGE siRNA ( Figure 5F).…”

Endoplasmic reticulum stress of Kupffer cells involved in the conversion of natural regulatory T cells to Th17 cells in liver ischemia‐reperfusion injury

“…[1][2][3] Although the knowledge on IRI is expanding, the transformation of injury signal from metabolic stress to inflammation remains appreciated. 1 Endoplasmic reticulum (ER) stress was proved to be implicated in the IRI of organs.…”

“…1,6 Recently, ER stress of Kupffer cells (KCs) was proved to mediate inflammation by activating Toll-like receptors at the early stage of liver IRI. 3 Indeed, KC-derived cytotoxic molecule-mediated hepatocellular injury was commonly considered as the first step in immune insult, although opposite pro-and anti-inflammatory functions of KCs were identified, often in an IR-stage-dependent manner. 7,8 These seemingly distinct processes of liver IRI were integrated into the unified outcome, that is, increased pro-inflammatory factors and decreased anti-inflammatory factors.…”