Targeting IRE1 endoribonuclease activity alleviates cardiovascular lesions in a murine model of Kawasaki disease vasculitis

Marek-Iannucci, Stefanie; Yıldırım, Aslı; Hamid, Syed Muhammad; Ozdemir, Asli Beyza; Gómez, Alejandro Raúl Gratacós; Kocatürk, Begüm; Porritt, Rebecca A.; Fishbein, Michael C.; Rivas, Magali Noval; Erbay, Ebru; Arditi, Moshe

doi:10.1172/jci.insight.157203

Cited by 14 publications

(8 citation statements)

References 62 publications

(134 reference statements)

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“…Taken together, the results have demonstrated that three ER stress pathways, ATF6, PERK, and IRE1, participate in the pathogenesis of human aortic aneurysms and mouse Ang II abdominal aortic and thoracic aneurysms. Our findings are well correlated with previous reports in patients with AAA ( 26 ), and AAA mouse models, including VSMC-specific IRE1 downstream transcription factor X-box binding protein 1 (XBP1) ( 58 )-KO mice ( 27 ), myeloid-specific IRE1-KO mice ( 28 ), VSMC-specific gasdermin D (GSDMD)-KO mice ( 59 ), and elastase-induced AAA treated with a PERK inhibitor ( 29 ) ( Figure 4I ).…”

Section: Resultssupporting

confidence: 91%

“…Although some downstream regulators of ER stress, including XBP1 ( 27 ), IRE1 ( 28 ), or PERK ( 29 ), have been identified as potential targets for AAA, the detailed molecular mechanisms of experimentally verified ER stress genes in specific areas of the aorta (abdominal or thoracic aorta) are poorly documented. We hypothesized that ER stress-induced genes partially overlapped with upregulated genes in Ang II abdominal AA and thoracic AA.…”

Section: Resultsmentioning

confidence: 99%

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ER stress mediates Angiotensin II-augmented innate immunity memory and facilitates distinct susceptibilities of thoracic from abdominal aorta to aneurysm development

Lu,

Sun,

Saaoud

et al. 2023

Front. Immunol.

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To determine the roles of endoplasmic reticulum (ER) stress and trained immunity, we performed transcriptome analyses on the thoracic aorta (TA) and abdominal aorta (AA) from the angiotensin II (Ang II)-HFD-ApoE-KO aneurysm model and made significant findings: 1) Ang II bypassed HFD-induced metabolic reprogramming and induced stronger inflammation in AA than in TA; 2) Ang II and HFD upregulated 890 genes in AA versus TA and induced cytokine signaling; 3) Ang II AA and TA upregulated 73 and 68 cytokines, scRNA-Seq identified markers of macrophages and immune cells, cell death regulators, respectively; transdifferentiation markers of neuron, glial, and squamous epithelial cells were upregulated by Ang II-AA and TA; and pyroptosis signaling with IL-1β and caspase-4 were more upregulated in Ang II-AA than in TA; 4) Six upregulated transcriptomes in patients with AAA, Ang II AA, Ang II TA, additional aneurysm models, PPE-AAA and BAPN-Ang II-AAA, were partially overlapped with 10 lists of new ER stress gene sets including 3 interaction protein lists of ER stress regulators ATF6, PERK, and IRE1, HPA ER localization genes, KEGG signal genes, XBP1 transcription targets, ATF4 (PERK) targets, ATF6 targets, thapsigargin ER stress genes, tunicamycin-ER stress genes, respectively; 5) Ang II-AA and TA upregulated ROS regulators, MitoCarta genes, trained immunity genes, and glycolysis genes; and 6) Gene KO transcriptomes indicated that ATF6 and PERK played more significant roles than IRE1 in promoting AAA and trained immunity whereas antioxidant NRF2 inhibited them. Our unprecedented ER-focused transcriptomic analyses have provided novel insights on the roles of ER as an immune organelle in sensing various DAMPs and initiating ER stress that triggers Ang II-accelerated trained immunity and differs susceptibilities of thoracic and abdominal aortas to diseases.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

ER stress mediates Angiotensin II-augmented innate immunity memory and facilitates distinct susceptibilities of thoracic from abdominal aorta to aneurysm development

Lu,

Sun,

Saaoud

et al. 2023

Front. Immunol.

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“…Our study is not the first to demonstrate that Ire1a downregulation can decrease UPR-mediated cell death. Inhibiting Ire1a activity in a mouse model of Kawasaki disease vasculitis was sufficient to decrease cell death [40]. Furthermore, in a human acute myeloid leukemia study, patients that had defective CEBPA double mutants had increased Ire1a expression [41].…”

Section: Discussionmentioning

confidence: 96%

CEBPA Overexpression Enhances β-Cell Proliferation and Survival

Ellsworth,

Herring,

Leifer

et al. 2024

Biology

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A commonality between type 1 and type 2 diabetes is the decline in functional β-cell mass. The transcription factor Nkx6.1 regulates β-cell development and is integral for proper β-cell function. We have previously demonstrated that Nkx6.1 depends on c-Fos mediated upregulation and the nuclear hormone receptors Nr4a1 and Nr4a3 to increase β-cell insulin secretion, survival, and replication. Here, we demonstrate that Nkx6.1 overexpression results in upregulation of the bZip transcription factor CEBPA and that CEBPA expression is independent of c-Fos regulation. In turn, CEBPA overexpression is sufficient to enhance INS-1 832/13 β-cell and primary rat islet proliferation. CEBPA overexpression also increases the survival of β-cells treated with thapsigargin. We demonstrate that increased survival in response to ER stress corresponds with changes in expression of various genes involved in the unfolded protein response, including decreased Ire1a expression. These data show that CEBPA is sufficient to enhance functional β-cell mass by increasing β-cell proliferation and modulating the unfolded protein response.

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“…Overall, their findings show that pharmacological or genetic suppression of IRE1 signaling in macrophages lowers NLRP3 inflammasome activation and mRNA expression of inflammatory cytokine caused by LCWE. In addition, LCWE‐injected LysM Cre+ Ern1 Δ/Δ animals had lower blood IL‐1β levels and caspase‐1 activity compared to their Ern1 fl/fl littermate control counterparts (Marek‐Iannucci et al, 2022).…”

Section: Nlrp3 and Kdmentioning

confidence: 98%

“…Also, it has been shown that stimulation of macrophages with saturated fatty acid leads to activation of NLRP3 and IL‐1β due to RNase activity of IRE1 (Robblee et al, 2016; Tufanli et al, 2017). Owing to these associations between IRE1 activity during ER stress and NLRP3 activation, Marek‐Iannucci et al (2022) hypothesized that IRE1 activation might play a role in the pathogenesis of KD. They showed, using single‐cell RNA sequencing (scRNA‐seq) study of abdominal aortas and spatial transcriptomics of heart tissues, that myeloid cells infiltrating the cardiovascular lesions of LCWE‐injected animals coexpress NLRP3, PYCARD, caspase1, and IL‐1β and are probably the source of IL‐1β.…”

Section: Nlrp3 and Kdmentioning

confidence: 99%

Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease

Shahi

Afzali

Firoozi

et al. 2023

Journal Cellular Physiology

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There is a heterogeneous group of rare illnesses that fall into the vasculitis category and are characterized mostly by blood vessel inflammation. Ischemia and disrupted blood flow will cause harm to the organs whose blood arteries become inflamed. Kawasaki disease (KD) is the most prevalent kind of vasculitis in children aged 5 years or younger. Because KD's cardiovascular problems might persist into adulthood, it is no longer thought of as a self‐limiting disease. KD is a systemic vasculitis with unknown initiating factors. Numerous factors, such as genetic predisposition and infectious pathogens, are implicated in the etiology of KD. As endothelial cell damage and inflammation can lead to coronary endothelial dysfunction in KD, some studies hypothesized the crucial role of pyroptosis in the pathogenesis of KD. Additionally, pyroptosis‐related proteins like caspase‐1, apoptosis‐associated speck‐like protein containing a CARD (ASC), proinflammatory cytokines like IL‐1 and IL‐18, lactic dehydrogenase, and Gasdermin D (GSDMD) have been found to be overexpressed in KD patients when compared to healthy controls. These occurrences may point to an involvement of inflammasomes and pyroptotic cell death in the etiology of KD and suggest potential treatment targets. Based on these shreds of evidence, in this review, we aim to focus on one of the well‐defined inflammasomes, NLRP3, and its role in the pathophysiology of KD.

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Targeting IRE1 endoribonuclease activity alleviates cardiovascular lesions in a murine model of Kawasaki disease vasculitis

Cited by 14 publications

References 62 publications

ER stress mediates Angiotensin II-augmented innate immunity memory and facilitates distinct susceptibilities of thoracic from abdominal aorta to aneurysm development

ER stress mediates Angiotensin II-augmented innate immunity memory and facilitates distinct susceptibilities of thoracic from abdominal aorta to aneurysm development

CEBPA Overexpression Enhances β-Cell Proliferation and Survival

Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease

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