Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus

Patrick, David M.; Visitación, Néstor de la; Krishnan, Jaya; Chen, Wei; Ormseth, Michelle J.; Stein, C. Michael; Davies, Sean S.; Amarnath, V.; Crofford, Leslie J.; Williams, Jonathan M.; Zhao, Shilin; Smart, Charles D; Dikalov, Sergey; Dikalova, Anna; Xiao, Liang; Beusecum, Justin P Van; Ao, Mingfang; Fogo, Agnes B.; Kirabo, Annet; Harrison, David G.

doi:10.1172/jci.insight.136678

Cited by 24 publications

(29 citation statements)

References 67 publications

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“…Importantly, scavenging of isoLG adducts attenuates additional pathologies associated with NETosis including atherosclerosis and SLE. 19,35 NETs are a component of the atherosclerotic plaque and contribute to endothelial cell damage and plaque erosion. 36,37 Atherosclerosis prone Ldlr − /− mice treated with 2HOBA exhibited reduced isoLG adduct accumulation within the atherosclerotic aorta in addition to stabilized atherosclerotic plaques.…”

Section: Discussionmentioning

confidence: 99%

“…40 In humans with SLE, isoLG adducts markedly accumulate within antigen-presenting cells. 35 Both B6.SLE123 and the NZBW/F1 mouse models of SLE exhibit a reduction in renal inflammation and lupus disease activity in addition to attenuated hypertension when treated with 2HOBA. 35 These studies strongly support a role of isoLGs as a primary component of neutrophil and NET driven systemic inflammation and disease processes.…”

Section: Discussionmentioning

confidence: 99%

“…35 Both B6.SLE123 and the NZBW/F1 mouse models of SLE exhibit a reduction in renal inflammation and lupus disease activity in addition to attenuated hypertension when treated with 2HOBA. 35 These studies strongly support a role of isoLGs as a primary component of neutrophil and NET driven systemic inflammation and disease processes. The demonstration that isoLGs autonomously drive NETosis suggests that the effects of 2HOBA in these disease conditions is secondary to the initial insult of isoLG formation within neutrophils.…”

Section: Discussionmentioning

confidence: 99%

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IsoLGs (Isolevuglandins) Drive Neutrophil Migration in Hypertension and Are Essential for the Formation of Neutrophil Extracellular Traps

et al. 2022

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Background: IsoLGs (isolevuglandins) are electrophilic products of lipid peroxidation formed in the presence of reactive oxygen species. IsoLGs contribute to hypertension by an unknown mechanism. Studies have shown that reactive oxygen species production drives the formation of neutrophil extracellular traps (NETs) and that NETs accumulate within the aorta and kidneys of patients with hypertension. The purpose of this study was to determine the role of isoLGs in neutrophil migration and NET formation (NETosis) in hypertension. Methods: Mice were treated with Ang II (angiotensin II) and the specific isoLG scavenger 2-hydroxybenzylamine and examined for tissue neutrophil and NET accumulation by single-cell sequencing and flow cytometry. Isolated human neutrophils were studied to determine the role of isoLGs in NETosis and neutrophil chromatin expansion by immunofluorescence and live cell confocal microscopy. Results: Single-cell sequencing performed on sham, Ang II, and Ang II+2-hydroxybenzylamine treated mice revealed neutrophils as a primary target of 2-hydroxybenzylamine. Peripheral neutrophil migration, aortic NET accumulation, and renal NET accumulation is blocked with 2-hydroxybenzylamine treatment. In isolated human neutrophils, isoLGs accumulate during NETosis and scavenging of isoLGs prevents NETosis. IsoLGs drive neutrophil chromatin expansion during NETosis and disrupt nucleosome structure. Conclusions: These observations identified a critical role of isoLGs in neutrophil migration and NETosis in hypertension and provide a potential therapy for NET-associated diseases including hypertension and associated end organ damage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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IsoLGs (Isolevuglandins) Drive Neutrophil Migration in Hypertension and Are Essential for the Formation of Neutrophil Extracellular Traps

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“…Such an inflammatory response may increase susceptibility to AD, especially among those carrying genetic risk variants. As CRP activates the complement system [65] and the activated complement system is involved in AD pathogenesis [66], all three genes, SPI1 [67], CD33 [68] and CLU [69], are linked with complement in proinflammation, suggesting a common cross-shared pathway for all of these factors in AD. Since it is currently unrealistic to Fig.…”

Section: Discussionmentioning

confidence: 99%

The impact of increasing levels of blood C-reactive protein on the inflammatory loci SPI1 and CD33 in Alzheimer’s disease

et al. 2022

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Apolipoprotein ε4 (APOE ε4) is the most significant genetic risk factor for late-onset Alzheimer’s disease (AD). Elevated blood C-reactive protein (CRP) further increases the risk of AD for people carrying the APOE ε4 allele. We hypothesized that CRP, as a key inflammatory element, could modulate the impact of other genetic variants on AD risk. We selected ten single nucleotide polymorphisms (SNPs) in reported AD risk loci encoding proteins related to inflammation. We then tested the interaction effects between these SNPs and blood CRP levels on AD incidence using the Cox proportional hazards model in UK Biobank (n = 279,176 white participants with 803 incident AD cases). The five top SNPs were tested for their interaction with different CRP cutoffs for AD incidence in the Framingham Heart Study (FHS) Generation 2 cohort (n = 3009, incident AD = 156). We found that for higher concentrations of serum CRP, the AD risk increased for SNP genotypes in 3 AD-associated genes (SPI1, CD33, and CLU). Using the Cox model in stratified genotype analysis, the hazard ratios (HRs) for the association between a higher CRP level (≥10 vs. <10 mg/L) and the risk of incident AD were 1.94 (95% CI: 1.33–2.84, p < 0.001) for the SPI1 rs1057233-AA genotype, 1.75 (95% CI: 1.20–2.55, p = 0.004) for the CD33 rs3865444-CC genotype, and 1.76 (95% CI: 1.25–2.48, p = 0.001) for the CLU rs9331896-C genotype. In contrast, these associations were not observed in the other genotypes of these genes. Finally, two SNPs were validated in 321 Alzheimer’s Disease Neuroimaging (ADNI) Mild Cognitive Impairment (MCI) patients. We observed that the SPI1 and CD33 genotype effects were enhanced by elevated CRP levels for the risk of MCI to AD conversion. Furthermore, the SPI1 genotype was associated with CSF AD biomarkers, including t-Tau and p-Tau, in the ADNI cohort when the blood CRP level was increased (p < 0.01). Our findings suggest that elevated blood CRP, as a peripheral inflammatory biomarker, is an important moderator of the genetic effects of SPI1 and CD33 in addition to APOE ε4 on AD risk. Monitoring peripheral CRP levels may be helpful for precise intervention and prevention of AD for these genotype carriers.

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“…In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduced transcription of all C1q subunits. Treatment of SLE mice with the specific isoLG scavenger 2-hydroxybenzylamine (2-HOBA) ameliorated parameters of autoimmunity, including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers ( 29 ). This result also indicates the potential pathogenic role of PU.1 in SLE.…”

Section: The Role Of Pu1 In Autoimmune Diseasesmentioning

confidence: 99%

The role of a key transcription factor PU.1 in autoimmune diseases

Fang

Chen

et al. 2022

Front. Immunol.

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PU.1, a transcription factor member of the E26 transformation-specific family, affects the function of a variety of immune cells in several physiological and pathological conditions. Previous studies studying the role of PU.1 in pathological conditions have mainly focused on immune system-related cancers, and a series of articles have confirmed that PU.1 mutation can induce a variety of immune cell-related malignancies. The underlying mechanism has also been extensively validated. However, the role of PU.1 in other major immune system-related diseases, namely, systemic autoimmune diseases, is still unclear. It was only in recent years that researchers began to gradually realize that PU.1 also played an important role in a variety of autoimmune diseases, such as rheumatoid arthritis (RA), experimental autoimmune encephalomyelitis (EAE) and systemic lupus erythematosus (SLE). This review article summarizes the findings of recent studies that investigated the role of PU.1 in various autoimmune diseases and the related underlying mechanisms. Furthermore, it presents new ideas and provides insight into the role of PU.1 as a potential treatment target for autoimmune diseases and highlights existing research problems and future research directions in related fields.

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Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus

Cited by 24 publications

References 67 publications

IsoLGs (Isolevuglandins) Drive Neutrophil Migration in Hypertension and Are Essential for the Formation of Neutrophil Extracellular Traps

IsoLGs (Isolevuglandins) Drive Neutrophil Migration in Hypertension and Are Essential for the Formation of Neutrophil Extracellular Traps

The impact of increasing levels of blood C-reactive protein on the inflammatory loci SPI1 and CD33 in Alzheimer’s disease

The role of a key transcription factor PU.1 in autoimmune diseases

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