The Complement System, Aging, and Aging-Related Diseases

Zheng, Runzi; Zhang, Yanghuan; Zhang, Ke; Yang, Yuan; Jia, Shuting; Liu, Jing

doi:10.3390/ijms23158689

Cited by 37 publications

(29 citation statements)

References 117 publications

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“…C3 protein plays a central role in the activation of the complement system. The complement is a part of the immune system and consists of multiple components with biological functions such as defense against pathogens and immunomodulation (Zheng et al, 2022). The complement system is an ancient defense mechanism present in invertebrates and vertebrate (Bavia et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Role of glucocorticoid and mineralocorticoid receptors in rainbow trout (Oncorhynchus mykiss) skeletal muscle: A transcriptomic perspective of cortisol action

et al. 2023

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Cortisol is an essential regulator of neuroendocrine stress responses in teleost. Cortisol performs its effects through the modulation of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), activating gene expression. Until now the contribution of both receptors in the global transcriptional response in teleost skeletal muscle has not been explored. To understand in a comprehensive and global manner how GR and MR modulates the skeletal muscle transcriptomic response, we performed RNA-seq analysis. Juvenile rainbow trout (Oncorhynchus mykiss) pretreated with a suppressor of endogenous cortisol production were intraperitoneally injected with cortisol (10 mg/kg). We also included a treatment with mifepristone (GR antagonist) and eplerenone (MR antagonist) in the presence or absence of cortisol. cDNA libraries were constructed from the skeletal muscle of rainbow trout groups: vehicle, cortisol, mifepristone, eplerenone, mifepristone/cortisol and eplerenone/cortisol. RNA-seq analysis revealed that 135 transcripts were differentially expressed in cortisol vs. mifepristone/cortisol group, mainly associated to inflammatory response, ion transmembrane transport, and proteolysis. In the other hand, 68 transcripts were differentially expressed in cortisol vs. eplerenone/cortisol group, mainly associated to muscle contraction, and regulation of cell cycle. To validate these observations, we performed in vitro experiments using rainbow trout myotubes. In myotubes treated with cortisol, we found increased expression of cxcr2, c3, and clca3p mediated by GR, associated with inflammatory response, proteolysis, and ion transmembrane transport, respectively. Contrastingly, MR modulated the expression of myh2 and gadd45g mainly associated with muscle contraction and regulation of cell cycle, respectively. These results suggest that GR and MR have a differential participation in the physiological response to stress in teleost skeletal muscle.

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Section: Discussionmentioning

confidence: 99%

Role of glucocorticoid and mineralocorticoid receptors in rainbow trout (Oncorhynchus mykiss) skeletal muscle: A transcriptomic perspective of cortisol action

et al. 2023

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“…In the developing brain, the complement is involved in synaptic pruning mediated by microglial cells ( 48 ). This physiological process of eliminating unwanted synapses has been shown to be aberrantly activated in aging brain and in neurodegenerative diseases as well as in progressive MS ( 49 – 52 ). In a mouse model of AD, it has been shown that C1q, the initiating protein of the classical complement, is increased and associated with synapses before overt plaque deposition ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid proteomics in recent-onset Narcolepsy type 1 reveals activation of the complement system

et al. 2023

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IntroductionNarcolepsy type 1 (NT1) is a rare, chronic and disabling neurological disease causing excessive daytime sleepiness and cataplexy. NT1 is characterized pathologically by an almost complete loss of neurons producing the orexin neuropeptides in the lateral hypothalamus. Genetic and environmental factors strongly suggest the involvement of the immune system in the loss of orexin neurons. The cerebrospinal fluid (CSF), secreted locally and surrounding the central nervous system (CNS), represents an accessible window into CNS pathological processes.MethodsTo gain insight into the biological and molecular changes in NT1 patients, we performed a comparative proteomics analysis of the CSF from 21 recent-onset NT1 patients and from two control groups: group 1 with somatoform disorders, and group 2 patients with hypersomnia other than NT1, to control for any potential effect of sleep disturbances on CSF composition. To achieve an optimal proteomic coverage analysis, the twelve most abundant CSF proteins were depleted, and samples were analyzed by nano-flow liquid chromatography tandem mass spectrometry (nano-LC-MS/MS) using the latest generation of hybrid Orbitrap mass spectrometer.Results and discussionOur study allowed the identification and quantification of up to 1943 proteins, providing a remarkably deep analysis of the CSF proteome. Interestingly, gene set enrichment analysis indicated that the complement and coagulation systems were enriched and significantly activated in NT1 patients in both cohorts analyzed. Notably, the lectin and alternative complement pathway as well as the downstream lytic membrane attack complex were congruently increased in NT1. Our data suggest that the complement dysregulation in NT1 patients can contribute to immunopathology either by directly promoting tissue damage or as part of local inflammatory responses. We therefore reveal an altered composition of the CSF proteome in NT1 patients, which points to an ongoing inflammatory process contributed, at least in part, by the complement system.

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“…Interestingly, we found three components ( C6, C8A, C8B ) of the complement system’s Membrane Attack Complex (MAC) among the shared downregulated genes. Few studies have examined how the complement system changes with aging 51 . Our finding that multiple components of MAC are downregulated with aging suggests that this could be functionally linked with aging.…”

Section: Main Textmentioning

confidence: 99%

miR-29 is an important driver of aging-related phenotypes

Swahari

Nakamura

Hollville

et al. 2022

Preprint

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Aging is a consequence of complex molecular changes, but the roles of individual microRNAs (miRNAs) in aging remain unclear. One of the few miRNAs that are upregulated during both normal and premature aging is miR-29. We confirmed this finding in our study in both mouse and monkey models. Follow-up analysis of the transcriptomic changes during normal aging revealed that miR-29 is among the top miRNAs predicted to drive the aging-related gene expression changes. We also showed that partial loss of miR-29 extends the lifespan of Zmpste24-/- mice, an established model of progeria, which indicates that miR-29 is functionally important in this accelerated aging model. To examine whether miR-29 upregulation alone is sufficient to promote aging-related phenotypes in vivo, we generated mice in which miR-29 can be conditionally overexpressed (miR-29TG). We found that miR-29 overexpression in mice is sufficient to drive aging-related phenotypes including alopecia, kyphosis, osteoporosis, senescence, and leads to early lethality. Transcriptomic analysis of both young miR-29TG and old WT mice revealed shared downregulation of genes enriched in extracellular matrix and fatty acid metabolism, and shared upregulation of genes in pathways linked to inflammation. Together, these results highlight the functional importance of miR-29 in controlling a gene expression program that drives aging-related phenotypes.

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The Complement System, Aging, and Aging-Related Diseases

Cited by 37 publications

References 117 publications

Role of glucocorticoid and mineralocorticoid receptors in rainbow trout (Oncorhynchus mykiss) skeletal muscle: A transcriptomic perspective of cortisol action

Role of glucocorticoid and mineralocorticoid receptors in rainbow trout (Oncorhynchus mykiss) skeletal muscle: A transcriptomic perspective of cortisol action

Cerebrospinal fluid proteomics in recent-onset Narcolepsy type 1 reveals activation of the complement system

miR-29 is an important driver of aging-related phenotypes

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