Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation.
Rajesh Kumar Gandhirajan,Shu Meng,Harish C. Chandramoorthy,Karthik Mallilankaraman,Salvatore Mancarella,Hui Gao,Roshanak Razmpour,Xiaofeng Yang,Steven R. Houser,Ju Chen,Walter J. Koch,Hong Wang,Jonathan Soboloff,Donald L. Gill,Muniswamy Madesh +14 more
TLDR
The results indicate that ROS-driven Ca2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI.Abstract:
During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca2+ overload. Despite considerable investigation, the underlying molecular mechanism(s) leading to LPS-induced ALI remain elusive. To determine whether stromal interaction molecule 1-dependent (STIM1-dependent) signaling drives endothelial dysfunction in response to LPS, we investigated oxidative and STIM1 signaling of EC-specific Stim1-knockout mice. Here we report that LPS-mediated Ca2+ oscillations are ablated in ECs deficient in Nox2, Stim1, and type II inositol triphosphate receptor (Itpr2). LPS-induced nuclear factor of activated T cells (NFAT) nuclear accumulation was abrogated by either antioxidant supplementation or Ca2+ chelation. Moreover, ECs lacking either Nox2 or Stim1 failed to trigger store-operated Ca2+ entry (SOCe) and NFAT nuclear accumulation. LPS-induced vascular permeability changes were reduced in EC-specific Stim1-/- mice, despite elevation of systemic cytokine levels. Additionally, inhibition of STIM1 signaling prevented receptor-interacting protein 3-dependent (RIP3-dependent) EC death. Remarkably, BTP2, a small-molecule calcium release-activated calcium (CRAC) channel blocker administered after insult, halted LPS-induced vascular leakage and pulmonary edema. These results indicate that ROS-driven Ca2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI.read more
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Journal ArticleDOI
Calcium and ROS: A mutual interplay.
TL;DR: Increasing evidence suggests a mutual interplay between calcium and ROS signaling systems which seems to have important implications for fine tuning cellular signaling networks.
Journal ArticleDOI
Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity
Zhiwei Dong,Santhanam Shanmughapriya,Dhanendra Tomar,Naveed Siddiqui,Solomon Lynch,Neeharika Nemani,Sarah L. Breves,Xue-Qian Zhang,Aparna Tripathi,Palaniappan Palaniappan,Massimo F. Riitano,Alison M. Worth,Ajay Seelam,Edmund Carvalho,Ramasamy Subbiah,Fabián Jaña,Jonathan Soboloff,Yizhi Peng,Joseph Y. Cheung,Suresh K. Joseph,Jeffrey L. Caplan,Sudarsan Rajan,Peter B. Stathopulos,Muniswamy Madesh +23 more
TL;DR: Both oxidation and mutation of MCU Cys-97 exhibited persistent MCU channel activity with higher [Ca2+]m uptake rate, elevated mROS, and enhanced [Ca1-m overload-induced cell death, and these effects were largely independent ofMCU interaction with its regulators.
Journal ArticleDOI
Crosstalk between calcium and reactive oxygen species signaling in cancer.
Nadine Hempel,Mohamed Trebak +1 more
TL;DR: The regulation of Ca2+ channels and transporters by oxidants are described and the potential consequences of the ROS-Ca2+ interplay in tumor cells are discussed.
Journal ArticleDOI
Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex.
So Yeon Kim,Jong Min Jeong,Soo Jin Kim,Wonhyo Seo,Myung Ho Kim,Won Mook Choi,Wonbeak Yoo,Jun Hee Lee,Young Ri Shim,Hyon-Seung Yi,Young-Sun Lee,Hyuk Soo Eun,Byung Seok Lee,Kwangsik Chun,Suk-Jo Kang,Sun Chang Kim,Bin Gao,George Kunos,Ho Min Kim,Won-Il Jeong +19 more
TL;DR: Palmitate binds a monomeric TLR4–MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1β expression in macrophages, which might be a novel therapeutic target for non-alcoholic fatty liver disease.
Journal ArticleDOI
Necroptosis, in vivo detection in experimental disease models.
Sandrine Jouan-Lanhouet,Franck B. Riquet,Linde Duprez,Tom Vanden Berghe,Nozomi Takahashi,Peter Vandenabeele +5 more
TL;DR: This review will present the last methodological advances for in vivo necroptosis identification and discuss past and recent data to provide an update of the so-called "necroptotic-associated pathologies".
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