Complement C3a receptor–mediated vascular dysfunction: a complex interplay between aging and neurodegeneration

Bhatia, Kanchan; Ahmad, Saif; Kindelin, Adam; Ducruet, Andrew F.

doi:10.1172/jci144348

Cited by 20 publications

(14 citation statements)

References 13 publications

(16 reference statements)

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“…C3a/C3aR signaling via intracellular Ca 2+ mediates vascular endothelial cadherin junction and barrier integrity in an in vitro model of the BBB. Microglial reactivity can be inhibited by inactivation of C3aR1, and this restores hippocampal and cortical volumes in aged brains, suggesting an association between impaired BBB, inflammation, and neurodegeneration [334,335]. Complement plays complex roles in brain homeostasis and likely has both protective and exacerbating effects on disease [327].…”

Section: Complement In the Brainmentioning

confidence: 99%

Neuroinflammation in Alzheimer’s Disease

et al. 2021

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Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

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Section: Complement In the Brainmentioning

confidence: 99%

Neuroinflammation in Alzheimer’s Disease

et al. 2021

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“…Although elevated C3 levels were found in patients with depression [ 14 – 17 ], inconsistent results were also reported [ 18 – 22 ]. C3a is the major active product of C3 and recently found to be implicated in the impairment of blood–brain barrier integrity [ 23 ], which is considered as a potential pathophysiology of MDD [ 24 ]. Furthermore.…”

Section: Introductionmentioning

confidence: 99%

Plasma complement C3 and C3a are increased in major depressive disorder independent of childhood trauma

et al. 2022

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Background Dysregulated complement system is linked to pathophysiology of major depressive disorder (MDD). Childhood trauma has been associated with an increased incidence of adult depression via a putative mechanism of immune activation. This study aimed to measure and compare peripheral levels of complement C3, C3a, C1q and C-reactive protein (CRP) in MDD patients and healthy controls and explore the relationship between these molecule levels and childhood trauma history in the participants. Methods The participants were 49 medication-free MDD patients and 45 healthy controls. All participants were asked to finish the Childhood Trauma Questionnaire, followed by blood sampling for measurement of plasma complement C3, C3a, C1q and CRP by means of enzyme-linked immunosorbent assay. Results Peripheral plasma concentration of C3 and C3a in medication-free MDD group was significantly higher than that in the healthy controls; whereas the concentration of plasma C1q and CRP in depressed patients was comparable to that in healthy controls. All these inflammatory factors were not associated to childhood trauma experience in patients with MDD. Conclusion Our data suggest that complement C3 and C3a may be implicated in the pathophysiology of MDD, although traumatic childhood experiences were not associated with the circulating levels of complement C3, C3a, C1q and CRP.

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“…They can also influence pathological changes in the vasculature by regulating the same circadian regulation-related gene VCAM1 downstream of it. For example, the C3A/C3AR signaling axis regulates VCAM1 expression, which affects peripheral immune cell infiltration and alters the functional state of the vasculature ( 56 ). In contrast, upregulation of CCR1 expression on vascular smooth muscle can promote intimal injury through VCAM1, which plays an important role in vascular dysfunction and remodeling ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

Screening for key genes in circadian regulation in advanced atherosclerosis: A bioinformatic analysis

Yao

Liang

2023

Front. Cardiovasc. Med.

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BackgroundAtherosclerosis (AS) is the most important cardiovascular disease threatening human health, leading to adverse events such as myocardial infarction and stroke. The research on the pathogenesis and causes of AS is being improved step by step, and many factors are associated with AS. However, the relationship between circadian regulation and the pathogenesis of AS is still unclear. Our study identified 2 key genes of circadian regulation in AS by bioinformatics analysis, which provides new perspectives to understand the relationship between circadian rhythm and AS.MethodsWe downloaded samples of early and advanced AS from public databases, screened key genes by weighted gene co-expression network analysis (WGCNA) and Lasso, calculated the immune cell content of the samples using “CIBERSORT,” and analyzed the relationship between key genes and immune cells.ResultsWe obtained the most relevant core modules for advanced AS and analyzed the functions of these modules. Two circadian rhythm-related genes were obtained, which influence the immune infiltration of this late AS. ROC curves demonstrated the efficacy of key genes to differentiate between early and advanced AS.ConclusionWe identified 2 genes most associated with circadian rhythms in advanced AS, whose association with AS has not been elucidated and may become the next therapeutic target.

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Complement C3a receptor–mediated vascular dysfunction: a complex interplay between aging and neurodegeneration

Cited by 20 publications

References 13 publications

Neuroinflammation in Alzheimer’s Disease

Neuroinflammation in Alzheimer’s Disease

Plasma complement C3 and C3a are increased in major depressive disorder independent of childhood trauma

Screening for key genes in circadian regulation in advanced atherosclerosis: A bioinformatic analysis

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