Trends in Molecular Medicine
ReviewER stress-induced inflammation: does it aid or impede disease progression?
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
References (103)
Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis
J. Biol. Chem.
(2005)Signaling cell death from the endoplasmic reticulum stress response
Curr. Opin. Cell Biol.
(2011)- et al.
The two NF-kappaB activation pathways and their role in innate and adaptive immunity
Trends Immunol.
(2004) - et al.
Missing pieces in the NF-kappaB puzzle
Cell
(2002) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease
Cell
(2010)Inhibition of NF-kappaB by MG132 through ER stress-mediated induction of LAP and LIP
FEBS Lett.
(2011)Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis
J. Biol. Chem.
(2007)Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis
Cell
(2010)XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease
Cell
(2008)Mucins in the mucosal barrier to infection
Mucosal Immunol.
(2008)
Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2−/− mice
Dev. Biol.
A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort
Am. J. Hum. Genet.
New insights into the immunology of chronic obstructive pulmonary disease
Lancet
Induction of apoptosis by cigarette smoke via ROS-dependent endoplasmic reticulum stress and CCAAT/enhancer-binding protein-homologous protein (CHOP)
Free Radic. Biol. Med.
Early inflammation in the airways of a cystic fibrosis foetus
J. Cyst. Fibros.
Immunity, inflammation, and cancer
Cell
gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell cycle progression during colitis-associated tumorigenesis
Cancer Cell
Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice
Cancer Cell
IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer
Cancer Cell
Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation
J. Biol. Chem.
Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes
Trends Immunol.
Tumor entrained neutrophils inhibit seeding in the premetastatic lung
Cancer Cell
Alarmins link neutrophils and dendritic cells
Trends Immunol.
Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation
Biochim. Biophys. Acta
Decoding cell death signals in inflammation and immunity
Cell
Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications
Blood
Up-regulation of cyclooxygenase-2 and apoptosis resistance by p38 MAPK in hypericin-mediated photodynamic therapy of human cancer cells
J. Biol. Chem.
Signal transduction by the JNK group of MAP kinases
Cell
ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs
Mol. Cell
Targeting ER stress induced apoptosis and inflammation in cancer
Cancer Lett.
The unfolded protein response: from stress pathway to homeostatic regulation
Science
Nutrient sensing and inflammation in metabolic diseases
Nat. Rev. Immunol.
From endoplasmic-reticulum stress to the inflammatory response
Nature
NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha
Nature
Activators and target genes of Rel/NF-kappaB transcription factors
Oncogene
Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression
Mol. Cell. Biol.
Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2
Biol. Pharm. Bull.
Calreticulin exposure dictates the immunogenicity of cancer cell death
Nat. Med.
Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors
Nat. Med.
Activation of the Akt-NF-kappaB pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response
J. Immunol.
AP-1: a double-edged sword in tumorigenesis
Nat. Rev. Cancer
Function and regulation of AP-1 subunits in skin physiology and pathology
Oncogene
Acute phase response in animals: a review
Comp. Med.
Expression of acute-phase response proteins in retinal Muller cells in diabetes
Invest. Ophthalmol. Vis. Sci.
Lipopolysaccharide binding protein and serum amyloid A secretion by human intestinal epithelial cells during the acute phase response
J. Immunol.
Acute phase response induction by cancer treatment with photodynamic therapy
Int. J. Cancer
C-reactive protein: a critical update
J. Clin. Invest.
Macrophages, inflammation, and insulin resistance
Annu. Rev. Physiol.
A predominant role for parenchymal c-Jun amino terminal kinase (JNK) in the regulation of systemic insulin sensitivity
PLoS ONE
Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance
Proc. Natl. Acad. Sci. U.S.A.
Cited by (337)
Linarin ameliorates ischemia-reperfusion injury by the inhibition of endoplasmic reticulum stress targeting AKR1B1
2024, Brain Research Bulletin3D culture boosting fullerenol nanoparticles to induce calreticulin exposure on MCF-7 cells for enhanced macrophage-mediated cell removal
2023, Colloids and Surfaces B: BiointerfacesXBP1-mediated transcriptional regulation of SLC5A1 in human epithelial cells in disease conditions
2024, Cell and BioscienceMelatoninenhancedthecardioprotectiveeffectsofHTKsolution on Langendorff-perfused mouse hearts subjected to ischemia/ reperfusion
2024, Iranian Journal of Basic Medical Sciences
- *
These authors contributed equally to the work.