The endoplasmic reticulum: a sensor of cellular stress that modulates immune responses.

Many inflammatory and infectious diseases are characterized by the activation of signaling pathways steaming from the endoplasmic reticulum (ER). These pathways, primarily associated with loss of ER homeostasis, are emerging as key regulators of inflammation and infection. Recent advances shed light on the mechanisms linking ER-stress and immune responses

Inflammation initiated by stressed organelles.

Key cellular functions including those related to energy metabolism, organization of the genetic information or production of membrane-bound and secreted proteins are compartmentalized within organelles. Various stresses such as differentiation programs, viral and bacterial infections, perturbations in protein production, mechanical constraints, changes in the environment and nutriment accessibility can impact cellular homeostasis and organelle integrity. Perturbations of these cellular compartments trigger repair and adaptation programs aimed at restoring homeostasis. These events are often associated with low-grade inflammation also termed parainflammation. While the nature and mechanisms of danger signals released by irremediably damaged cells are well understood, how transiently stressed cells trigger inflammation is still poorly understood. Emerging studies highlighted new mechanisms by which stress pathways promote inflammation. Cytosolic innate immune pathways are engaged by signals stemming from perturbed organelles such as the mitochondria, the endoplasmic reticulum (ER) or the nuclear envelope (NE). These observations indicate that these pathways function as guardians of cellular homeostasis and may contribute to disease in pathologies characterized by perturbations of cellular homoeostasis. Mitochondria-stress, ER-stress or NE-stress are emerging as proinflammatory signals that contribute to human conditions and diseases

Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum.

The innate immune system has evolved the capacity to detect specific pathogens and to interrogate cell and tissue integrity in order to mount an appropriate immune response. Loss of homeostasis in the endoplasmic reticulum (ER) triggers the ER-stress response, a hallmark of many inflammatory and infectious diseases. The IRE1/XBP1 branch of the ER-stress signaling pathway has been recently shown to regulate and be regulated by innate immune signaling pathways in both the presence and absence of ER-stress. By contrast, innate immune pathways negatively affect the activation of two other branches of the ER-stress response as evidenced by reduced expression of the pro-apoptotic transcription factor CHOP. Here we will discuss how innate immune pathways and ER-signaling intersect to regulate the intensity and duration of innate immune responses

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations.

Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However, AIM2 achieves specificity by detecting altered or mislocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity. AIM2 is also a key sensor of pathogens that detects the presence of foreign DNA accumulating in the cytosol during the life cycle of intracellular pathogens including viruses, bacteria, and parasites. AIM2 activation initiates the assembly of the inflammasome, an innate immune complex that leads to the activation of inflammatory caspases. This triggers the maturation and secretion of the cytokines IL-1β and IL-18. It can also initiate pyroptosis, a proinflammatory form of cell death. The AIM2 inflammasome contributes to physiological responses and diseases. It is a key player in host defenses, but its deregulation can contribute immune-linked diseases, such as autoinflammatory and autoimmune pathologies. Moreover, AIM2 may play a role in cancer development. Recent studies have shown that the detection of self-DNA species by AIM2 is an important factor that contributes to diseases associated with perturbation of cellular homeostasis. Thus, in addition of being a sensor of pathogen associated molecular patterns (PAMPs), the AIM2 inflammasome is emerging as a key guardian of cellular integrity

A pilot study of IL-1 inhibition by anakinra in acute gout

Monosodium urate crystals stimulate monocytes and macrophages to release IL-1β through the NALP3 component of the inflammasome. The effectiveness of IL-1 inhibition in hereditary autoinflammatory syndromes with mutations in the NALP3 protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. IL-1 inhibition prevented peritoneal neutrophil accumulation but TNF blockade had no effect. Based on these findings, we performed a pilot, open-labeled study (trial registration number ISRCTN10862635) in 10 patients with gout who could not tolerate or had failed standard antiinflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. IL-1 blockade appears to be an effective therapy for acute gouty arthritis. The clinical findings need to be confirmed in a controlled study

Pharmacological eEF2K activation promotes cell death and inhibits cancer progression.

Activation of the elongation factor 2 kinase (eEF2K) leads to the phosphorylation and inhibition of the elongation factor eEF2, reducing mRNA translation rates. Emerging evidence indicates that the regulation of factors involved in protein synthesis may be critical for controlling diverse biological processes including cancer progression. Here we show that inhibitors of the HIV aspartyl protease (HIV-PIs), nelfinavir in particular, trigger a robust activation of eEF2K leading to the phosphorylation of eEF2. Beyond its anti-viral effects, nelfinavir has antitumoral activity and promotes cell death. We show that nelfinavir-resistant cells specifically evade eEF2 inhibition. Decreased cell viability induced by nelfinavir is impaired in cells lacking eEF2K. Moreover, nelfinavir-mediated anti-tumoral activity is severely compromised in eEF2K-deficient engrafted tumors in vivo Our findings imply that exacerbated activation of eEF2K is detrimental for tumor survival and describe a mechanism explaining the anti-tumoral properties of HIV-PIs

Impairment of both IRE1 expression and XBP1 activation is a hallmark of GCB DLBCL and contributes to tumor growth.

The endoplasmic reticulum kinase inositol-requiring enzyme 1 (IRE1) and its downstream target X-box-binding protein 1 (XBP1) drive B-cell differentiation toward plasma cells and have been shown to contribute to multiple myeloma development; yet, little is known of the role of this pathway in diffuse large B-cell lymphoma (DLBCL). Here, we show that in the germinal center B-cell-like (GCB) DLBCL subtype, IRE1 expression is reduced to a level that prevents XBP1 activation. Gene expression profiles indicated that, in GCB DLBCL cancer samples, expression of IRE1 messenger RNA was inversely correlated with the levels and activity of the epigenetic repressor, histone methyltransferase enhancer of zeste homolog 2 (EZH2). Correspondingly, in GCB-derived cell lines, the IRE1 promoter carried increased levels of the repressive epigenetic mark histone 3 lysine 27 trimethylation. Pharmacological inhibition of EZH2 erased those marks and restored IRE1 expression and function in vitro and in vivo. Moreover, reconstitution of the IRE1-signaling pathway, by expression of the XBP1-active form, compromised GCB DLBCL tumor growth in a mouse xenograft cancer model. These findings indicate that IRE1-XBP1 downregulation distinguishes GCB DLBCL from other DLBCL subtypes and contributes to tumor growth