Crosstalk Between ER Stress, Autophagy and Inflammation

Chipurupalli, Sandhya; Samavedam, Unni; Robinson, Nirmal

doi:10.3389/fmed.2021.758311

Cited by 86 publications

(64 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ER stress is a consequence of systemic inflammation ( Iwakoshi et al, 2003 ; Chipurupalli et al, 2021 ). ER stress leads to the activation of stress sensor proteins such as IRE1α, ATF6, and PERK, along with increased expression of UPR-related genes, such as GRP78 and CHOP ( Hosoi and Ozawa, 2012 ).…”

Section: Resultsmentioning

confidence: 99%

Peripheral Immune Activation in Mice Elicits Unfolded Protein Responses Independent on MyD88 Pathway in the Liver but not the Hypothalamus and Hippocampus

et al. 2022

View full text Add to dashboard Cite

Neuroimmune interactions between the immune system and CNS as well as peripheral organs such as the liver play a key role in the pathophysiological state of diseases. Unfolded protein responses (UPRs), which are activated by cells in response to endoplasmic reticulum stress, have been linked to the occurrence of inflammation diseases, neurodegenerative diseases, and metabolic disorders such as type 2 diabetes. Peripheral injection of lipopolysaccharide (LPS) is known to induce a systemic inflammatory response, along with fever, anorexia, and depressive behaviors. LPS also elicits UPRs, although the underlying physiological mechanism remains unclear. In the present study, we investigated whether peripheral activation of the immune system can elicit UPRs in the CNS and liver. Peripheral injection of LPS is known to elevate pro-inflammatory cytokines in the liver, hypothalamus and hippocampus. We report that LPS-induced systemic inflammation elicits UPRs in the liver, but not the hypothalamus. Injection of LPS upregulated the expression levels of glucose-regulated protein 78 and pro-apoptotic transcription factor C/EBP homologous protein, along with increased splicing of X-box binding protein one mRNA in the liver, but not in the hypothalamus and hippocampus. Myeloid differentiation primary response 88 (MyD88), an adaptor protein, is known to play a key role in the signal transduction of LPS mediated by Toll-like receptor 4. Using MyD88 deficient mice, we found that LPS-induced UPRs occurred independently of MyD88 expression. In summary, peripheral activation of the immune system elicits UPRs in the liver, but not the hypothalamus and hippocampus, which may have implications for the pathophysiology of diseases.

show abstract

Section: Resultsmentioning

confidence: 99%

Peripheral Immune Activation in Mice Elicits Unfolded Protein Responses Independent on MyD88 Pathway in the Liver but not the Hypothalamus and Hippocampus

et al. 2022

View full text Add to dashboard Cite

show abstract

“…ER stress-induced UPR signaling mediates inflammation via NF-κB. All three branches of the UPR activate NF-κB via gene transcription ( Hasnain et al, 2012 ; Chipurupalli et al, 2021 ). Under normal conditions, NF-κB forms a complex with inhibitor kappa B (ΙκΒ) and is unable to translocate to the nucleus and activate gene transcription.…”

Section: Er Stress and Inflammationmentioning

confidence: 99%

“…Initially, IRE1 branch is activated when the chaperone BiP that is usually bound to the three factors, IRE1, ATF6, and PERK, disengages due to the accumulation of misfolded proteins in the ER. This leads to the autophosphorylation of IRE1 and binding to adaptor protein, TRAF2, activating JNK/AKT pathways ( Hasnain et al, 2012 ; Chipurupalli et al, 2021 ). The IRE1/TRAF2 complex also activates ΙκΒ kinase, which phosphorylates IκB, leading to NF-κB nuclear translocation and cytokine expression.…”

Section: Er Stress and Inflammationmentioning

confidence: 99%

“…The IRE1/TRAF2 complex also activates ΙκΒ kinase, which phosphorylates IκB, leading to NF-κB nuclear translocation and cytokine expression. The autophosphorylation of PERK results in the expression of inflammatory cytokines interleukin (IL)-1, 6, and tumor necrosis factor alpha (TNF-α; Chipurupalli et al, 2021 ). CHOP which is activated within the PERK branch also regulates NF-κB.…”

Section: Er Stress and Inflammationmentioning

confidence: 99%

See 1 more Smart Citation

The Critical Roles of Proteostasis and Endoplasmic Reticulum Stress in Atrial Fibrillation

et al. 2022

View full text Add to dashboard Cite

Atrial fibrillation (AF) remains the most common arrhythmia seen clinically. The incidence of AF is increasing due to the aging population. AF is associated with a significant increase in morbidity and mortality, yet current treatment paradigms have proven largely inadequate. Therefore, there is an urgent need to develop new effective therapeutic strategies for AF. The endoplasmic reticulum (ER) in the heart plays critical roles in the regulation of excitation-contraction coupling and cardiac function. Perturbation in the ER homeostasis due to intrinsic and extrinsic factors, such as inflammation, oxidative stress, and ischemia, leads to ER stress that has been linked to multiple conditions including diabetes mellitus, neurodegeneration, cancer, heart disease, and cardiac arrhythmias. Recent studies have documented the critical roles of ER stress in the pathophysiological basis of AF. Using an animal model of chronic pressure overload, we demonstrate a significant increase in ER stress in atrial tissues. Moreover, we demonstrate that treatment with a small molecule inhibitor to inhibit the soluble epoxide hydrolase enzyme in the arachidonic acid metabolism significantly reduces ER stress as well as atrial electrical and structural remodeling. The current review article will attempt to provide a perspective on our recent understandings and current knowledge gaps on the critical roles of proteostasis and ER stress in AF progression.

show abstract

“…The involvement of the UPR in the pathogenesis of different myopathies such as Sporadic inclusion body myositis, Myasthenia gravis, Duchenne muscular dystrophy has been reviewed recently ( 137 ). In immune cells, ER stress and the UPR are implicated in the regulation of the inflammatory state ( 138 ). A couple of studies demonstrated that also in myocytes, proinflammatory stimuli regulate UPR signaling.…”

Section: Protein Quality Control Endoplasmic Reticulum Stress and The...mentioning

confidence: 99%

Hidden Agenda - The Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response in Inflammation-Induced Muscle Wasting

Kny

Fielitz

2022

Front. Immunol.

View full text Add to dashboard Cite

Critically ill patients at the intensive care unit (ICU) often develop a generalized weakness, called ICU-acquired weakness (ICUAW). A major contributor to ICUAW is muscle atrophy, a loss of skeletal muscle mass and function. Skeletal muscle assures almost all of the vital functions of our body. It adapts rapidly in response to physiological as well as pathological stress, such as inactivity, immobilization, and inflammation. In response to a reduced workload or inflammation muscle atrophy develops. Recent work suggests that adaptive or maladaptive processes in the endoplasmic reticulum (ER), also known as sarcoplasmic reticulum, contributes to this process. In muscle cells, the ER is a highly specialized cellular organelle that assures calcium homeostasis and therefore muscle contraction. The ER also assures correct folding of proteins that are secreted or localized to the cell membrane. Protein folding is a highly error prone process and accumulation of misfolded or unfolded proteins can cause ER stress, which is counteracted by the activation of a signaling network known as the unfolded protein response (UPR). Three ER membrane residing molecules, protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1a (IRE1a), and activating transcription factor 6 (ATF6) initiate the UPR. The UPR aims to restore ER homeostasis by reducing overall protein synthesis and increasing gene expression of various ER chaperone proteins. If ER stress persists or cannot be resolved cell death pathways are activated. Although, ER stress-induced UPR pathways are known to be important for regulation of skeletal muscle mass and function as well as for inflammation and immune response its function in ICUAW is still elusive. Given recent advances in the development of ER stress modifying molecules for neurodegenerative diseases and cancer, it is important to know whether or not therapeutic interventions in ER stress pathways have favorable effects and these compounds can be used to prevent or treat ICUAW. In this review, we focus on the role of ER stress-induced UPR in skeletal muscle during critical illness and in response to predisposing risk factors such as immobilization, starvation and inflammation as well as ICUAW treatment to foster research for this devastating clinical problem.

show abstract

Crosstalk Between ER Stress, Autophagy and Inflammation

Cited by 86 publications

References 93 publications

Peripheral Immune Activation in Mice Elicits Unfolded Protein Responses Independent on MyD88 Pathway in the Liver but not the Hypothalamus and Hippocampus

Peripheral Immune Activation in Mice Elicits Unfolded Protein Responses Independent on MyD88 Pathway in the Liver but not the Hypothalamus and Hippocampus

The Critical Roles of Proteostasis and Endoplasmic Reticulum Stress in Atrial Fibrillation

Hidden Agenda - The Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response in Inflammation-Induced Muscle Wasting

Contact Info

Product

Resources

About