CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

Faridi, Mohd Hafeez; Khan, Samia Q.; Zhao, Wenpu; Lee, Ha Won; Altintas, Mehmet M.; Zhang, Kun; Kumar, Vinay; Armstrong, Andrew; Carmona‐Rivera, Carmelo; Dorschner, Jessica M.; Schnaith, Abigail; Li, Xiaobo; Ghodke‐Puranik, Yogita; Moore, Eddie S.; Purmalek, Monica; Irizarry-Caro, Jorge A.; Zhang, Tingting; Day, Rachael; Stoub, Darren; Hoffmann, Victoria; Khaliqdina, Shehryar; Bhargava, Prachal; Santander, Ana M.; Torroella-Kouri, Marta; Issac, Biju; Cimbaluk, David; Zloza, Andrew; Prabhakar, Rajeev; Deep, Shashank; Jolly, Meenakshi; Koh, Kyung Bong; Reichner, Jonathan S.; Bradshaw, Elizabeth M.; Chen, Jianfeng; Moita, Luís F.; Yuen, Peter S.T.; Tsai, Wanxia Li; Singh, Bhupinder; Reiser, Jochen; Nath, Swapan K.; Niewold, Timothy B.; Vázquez-Padrón, Roberto I.; Kaplan, Mariana J.; Gupta, Vineet

doi:10.1172/jci88442

Cited by 91 publications

(89 citation statements)

References 77 publications

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“…Recent studies also suggest that inhibition of succinate dehydrogenase switches proinflammatory macrophage phenotype into an anti-inflammatory phenotype in which oxidative metabolism and IL-10 production are enhanced, while glycolysis, mitochondrial membrane potential, succinate oxidation, and mitochondrial ROS production are reduced [49]. Furthermore, the metabolism of plasmacytoid DCs (pDCs) can be drastically alterered by type I interferons (type I-IFNs; cytokines crucial in SLE pathogenesis [50–52]). Indeed, exposure to type I-IFNs induces an autocrine pathway of increased OXPHOS and type I-IFN production in pDCs, which is fueled by enhanced FAO and dependent on type I-IFN receptor and PPARα signaling [53].…”

Section: Metabolism Of Other Sle-associated Immune Cellsmentioning

confidence: 99%

“…, demonstrated that oxidized mtDNA has interferogenic potential through a STING-dependent pathway [51]. Various cell subsets and pathways have been shown to be drivers of type I-IFN production in lupus [50–52,73]. Despite the pathogenic role of type I-IFNs in SLE, these cytokines are crucial in the protection against viruses.…”

Section: Role Of Ros In Tissue Damage and Immune Cell Activation In Lmentioning

confidence: 99%

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Metabolic abnormalities and oxidative stress in lupus

Lightfoot

Blanco

Kaplan

2017

Current Opinion in Rheumatology

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Purpose of review Upon antigen exposure, immune cells rely on cell-specific metabolic pathways to mount an efficient immune response. In autoimmunity, failure in critical metabolic checkpoints may lead to immune cell hyper-activation and tissue damage. Oxidative stress in autoimmune patients can also contribute to immune dysregulation and injury to the host. Recent insights into the immune cell metabolism signatures specifically associated with systemic lupus erythematosus (SLE) and the consequences of heightened oxidative stress in patients are discussed herein. Recent findings Glucose metabolism inhibitors, mTOR pathway modulators, and PPARγ-activating compounds demonstrate therapeutic benefit in experimental models of lupus. Mitochondrial-derived reactive oxygen species (ROS) and molecular modifications induced by oxidative stress appear to be detrimental in lupus. Effective therapies tailored towards the reconfiguration of metabolic imbalances in lupus immune cells and the reduction of mitochondrial ROS production/availability are currently being tested. Summary A paucity of knowledge exists regarding the metabolic needs of a number of immune cells involved in the pathogenesis of SLE, including myeloid cells and B cells. Nonetheless, SLE-specific metabolic signatures have been identified and their specific targeting, along with mitochondrial ROS inhibitors/scavengers, could show therapeutic advantage in lupus patients.

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Section: Metabolism Of Other Sle-associated Immune Cellsmentioning

confidence: 99%

Section: Role Of Ros In Tissue Damage and Immune Cell Activation In Lmentioning

confidence: 99%

Metabolic abnormalities and oxidative stress in lupus

Lightfoot

Blanco

Kaplan

2017

Current Opinion in Rheumatology

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“…These agonists tend to induce an intermediate‐affinity conformation in Mac‐1 , which may permit neutrophil adhesion, with less potential for endothelial damage. Indeed, a partial Mac‐1 agonist not only protected MRL/lpr mice from end‐organ injury, but also enhanced endothelium‐dependent vasorelaxation and thereby demonstrated an overall vasoprotective effect . Taken together, these study findings indicate that targeting Mac‐1 might indeed be feasible and emphasize the need for future research in patients with APS.…”

Section: Discussionmentioning

confidence: 63%

Increased Adhesive Potential of Antiphospholipid Syndrome Neutrophils Mediated by β2 Integrin Mac‐1

Sule

Kelley

Gockman

et al. 2019

Arthritis & Rheumatology

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Objective While the role of antiphospholipid antibodies in activating endothelial cells has been extensively studied, the impact of these antibodies on the adhesive potential of leukocytes has received less attention. This study was undertaken to investigate the extent to which antiphospholipid syndrome (APS) neutrophils adhere to resting endothelial cells under physiologic flow conditions and the surface molecules required for that adhesion. Methods Patients with primary APS (n = 43), patients with a history of venous thrombosis but negative test results for antiphospholipid antibodies (n = 11), and healthy controls (n = 38) were studied. Cells were introduced into a flow chamber and perfused across resting human umbilical vein endothelial cells (HUVECs). Surface adhesion molecules were quantified by flow cytometry. Neutrophil extracellular trap release (NETosis) was assessed in neutrophil‐HUVEC cocultures. Results Upon perfusion of anticoagulated blood through the flow chamber, APS neutrophils demonstrated increased adhesion as compared to control neutrophils under conditions representative of either venous (n = 8; P < 0.05) or arterial (n = 15; P < 0.0001) flow. At the same time, APS neutrophils were characterized by up‐regulation of CD64, CEACAM1, β2‐glycoprotein I, and activated Mac‐1 on their surface (n = 12–18; P < 0.05 for all markers). Exposing control neutrophils to APS plasma or APS IgG resulted in increased neutrophil adhesion (n = 10–11; P < 0.0001) and surface marker up‐regulation as compared to controls. A monoclonal antibody specific for activated Mac‐1 reduced the adhesion of APS neutrophils in the flow‐chamber assay (P < 0.01). The same monoclonal antibody reduced NETosis in neutrophil–HUVEC cocultures (P < 0.01). Conclusion APS neutrophils demonstrate increased adhesive potential, which is dependent upon the activated form of Mac‐1. In patients, this could lower the threshold for neutrophil–endothelium interactions, NETosis, and possibly thrombotic events.

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“…При СКВ с «ранним началом» выявлена новая гомозиготная мутация с «потерей функции» (loss-of-function) гена комплемента 1R, которая характеризуется снижением концентрации комплемента и выраженной активацией синтеза ИФН типа I [43]. К другим недавно выявленным генетическим факторам, ассоциирующимся с активацией ИФН типа I при СКВ, относятся полиморфизмы гена пурин нуклеозид фосфатазы [44,45] и дефектной формы субъединицы интегрина альфа М (CD11b) [46]. Анализ эпигенетических изменений в CD4+ Т-лимфоцитов пациентов с СКВ выявил стойкое гипометилирование некоторых ISGs, ассоциирующихся с гиперреактивностью CD4+ лимфоцитов [47].…”

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Immunoinflammatory Rheumatic Diseases Associated With Type I Interferon: New Evidence

Насонов¹,

Авдеева²

2019

Naučno-praktičeskaâ revmatologiâ

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Иммуновоспалительные ревматические заболевания (ИВРЗ) -большая группа патологических состояний, в основе которых лежит нарушение иммунологической толерантности к собственным тканям, ведущее к воспалению и необратимым органным повреждениям. В обзоре рассмотрены современные представления о роли интерферонов типа I в иммунопатогенезе ИВРЗ, в первую очередь системной красной волчанки, и новые возможности персонифицированной терапии. Ключевые слова: иммуновоспалительные ревматические заболевания; интерфероны типа I; интерфероновый «автограф»; системная красная волчанка. Для ссылки: Насонов ЕЛ, Авдеева АС. Иммуновоспалительные ревматические заболевания, связанные с интерфероном типа I: новые данные. Научно-практическая ревматология. 2019;55(4):452-461.

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CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

Cited by 91 publications

References 77 publications

Metabolic abnormalities and oxidative stress in lupus

Metabolic abnormalities and oxidative stress in lupus

Increased Adhesive Potential of Antiphospholipid Syndrome Neutrophils Mediated by β2 Integrin Mac‐1

Immunoinflammatory Rheumatic Diseases Associated With Type I Interferon: New Evidence

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