Review
ER stress-induced inflammation: does it aid or impede disease progression?

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Different lines of research have revealed that pathways activated by the endoplasmic reticulum (ER) stress response induce sterile inflammation. When activated, all three sensors of the unfolded protein response (UPR), PERK, IRE1, and ATF6, participate in upregulating inflammatory processes. ER stress in various cells plays an important role in the pathogenesis of several diseases, including obesity, type 2 diabetes, cancer, and intestinal bowel and airway diseases. Moreover, it has been suggested that ER stress-induced inflammation contributes substantially to disease progression. However, this generalization can be challenged at least in the case of cancer. In this review, we emphasize that ER stress can either aid or impede disease progression via inflammatory pathways depending on the cell type, disease stage, and type of ER stressor.

Section snippets

Signaling behind ER stress-induced inflammation: from UPR sensors to inflammatory processes

Stress on the machinery of the ER can activate various processes, including the signaling pathway of the UPR and the integrated stress response. Most proteins that govern the integrity of the cell, the extracellular matrix, tissues, and the organism as a whole are processed through the ER, and the role of the ER tends to be particularly vital in immune cells because they produce a very large amount of protein. Thus, it is not surprising that induction of ER stress is communicated between the

ER stress-induced inflammation: from cell types to health and disease

Crosstalk between inflammation and ER stress-induced UPR probably influences pathogenesis and/or progression of diseases involving cells concerned with immune responses or metabolism (Figure 2). Cell types that are most influenced by such crosstalk include oligodendrocytes, macrophages, hepatocytes, pancreatic β-cells, and adipocytes [6]. Normal functioning of these cells requires the trafficking of large amounts of proteins through the ER, which makes them highly sensitive to perturbations in

Metabolic disorders and ER stress-induced inflammation

Obesity is accompanied by a broad array of inflammatory and stress responses in metabolic tissues, leading to chronic, low-grade local inflammation that plays a central role in inhibiting insulin receptor signaling and disrupting systemic metabolic homeostasis [15]. Accumulating data demonstrate a clear connection between inflammation and metabolic disorders. Experiments on obese mice have shown that adipocytes and macrophages in adipose tissue secrete a number of proinflammatory cytokines

Role of ER stress-induced inflammation in intestinal bowel diseases

Recent studies suggest that deregulation of UPR correlates with pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) (Figure 2), two major types of inflammatory bowel disease (IBD) 36, 37. Intestinal epithelial cells exposed to microbiota, as well as highly secretory cells such as Paneth cells 38, 39 and to a lesser extent goblet cells [40], are susceptible to ER stress.

Intestinal inflammation is linked to UPR by the IRE1 pathway. Deletion of the IRE1 gene in mouse intestinal

Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disease for which cigarette smoking is a major risk factor. It is characterized by progressive development of lung emphysema associated with an abnormal inflammatory response [47]. It has been shown that cigarette smoke induces UPR activation characterized in vitro by activation of the PERK-eIF2a branch and in vivo by P-eIF2a, CHOP induction, and upregulation of BiP and PDI 48, 49, 50, 51, 52, 53, 54. Of note, cigarette

Cancer cells and tumor-infiltrating immune cells: the yin and the yang of ER stress

Recent studies have shown that many types of tumors might require an inflammatory microenvironment mainly because inflammation can be protumorigenic [65]. Chronic inflammation in particular has been shown to promote the progress of tumors by influencing various stages of tumorigenesis. However, this might not apply to all kinds of tumors. For instance, in bladder cancer patients treated with Bacille Calmette-Guerin (BCG), acute inflammation has been shown to cause a reduction in tumor growth

Therapeutic targeting of ER stress-induced inflammation: a tough road ahead?

Targeting ER stress-induced inflammation is tricky for various reasons, three of which are prominent. (i) How can a particular cell type be targeted and at the same time the other cell types be spared? ER stress-induced inflammation is driven not only by immune cells but also by the cells involved in a particular pathology 3, 6, 15. Thus, topical or systemic therapeutic targeting of ER stress-mediated inflammation might be beneficial for the target cells but detrimental for the immune cells,

Concluding remarks

ER stress-induced inflammation mainly serves to control tissue damage and aid tissue repair. However, under certain conditions, its presence can promote the progression of diseases such as diabetes, obesity, IBD, inflammatory airway disease and cancer. Conversely, at least for cancer, ER stress can also instigate cancer-impeding antitumor immunity. Here, ER stress-induced inflammation can govern the longevity, intensity and type of immune responses, however, the final outcome of this

Disclaimer statement

The authors declare that there are no conflicts of interest.

Acknowledgments

We thank Dr Amin Bredan (DMBR-VIB, Ghent) for editing the manuscript. The work from the laboratory of A.D.G. was supported by a GOA grant (GOA/11/2010-2015) to P.A. This article also presents research results of the IAP6/18, funded by the Interuniversity Attraction Poles Programme initiated by the Belgian State, Science Policy Office. This work was supported by the Fund for Scientific Research Flanders [FWO-Vlaanderen, G072810N to P.A. and D.V.K.; 3G067512 to O.K. and D.V.K. and by an

Glossary

Acute-phase response (APR)
group of physiological processes occurring soon after the onset of infection, trauma, inflammation, and some malignant conditions. These processes include an increase in serum acute phase proteins (APPs) and vascular permeability, and development of fever, metabolic, neurological, and pathological changes.
Alarmins
endogenous ‘danger signals’ that mediate immunomodulatory processes after their release from cells undergoing cell death or after their secretion by

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