Complement dysregulation in the central nervous system during development and disease

Lee, John D.; Coulthard, Liam G.; Woodruff, Trent M.

doi:10.1016/j.smim.2019.101340

Cited by 82 publications

(94 citation statements)

References 185 publications

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“…These signalings may regulate the process of inflammation in the aged cochlea. The complement system is an important component of the immunity system, and chronic complement activation has been supposed to be associated with glial activation, and synapse and neuron loss in the aging central nervous system (Lee, Coulthard & Woodruff, 2019). Significant upregulation of complement proteins CFI and C1S was observed in noise-traumatized rat cochleae (Patel et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis highlights cochlear inflammation associated with age-related hearing loss in C57BL/6 mice using next generation sequencing

Xiong

Liu

et al. 2020

PeerJ

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Background In our aging society, age-related hearing loss (AHL) is the most common sensory disorder in old people. Much progress has been made in understanding the pathological process of AHL over the past few decades. However, the mechanism of cochlear degeneration during aging is still not fully understood. Methods Next generation sequencing technique was used to sequence the whole transcriptome of the cochlea of C57BL/6 mice, a mouse model of AHL. Differentially expressed genes (DEGs) were identified using the Cuffdiff software. GO and KEGG pathway enrichment analyses of the DEGs were implemented by using the GOseq R package and KOBAS software, respectively. Results A total of 731 genes (379 up- and 352 down-regulated) were revealed to be differentially expressed in the cochlea of aged mice compared to the young. Many genes associated with aging, apoptosis, necroptosis and particularly, inflammation were identified as being significantly modulated in the aged cochlea. GO and KEGG analyses of the upregulated DEGs revealed that the most enriched terms were associated with immune responses and inflammatory pathways, whereas many of the downregulated genes are involved in ion channel function and neuronal signaling. Real-time qPCR showed that H2O2 treatment significantly induced the expression of multiple inflammation and necroptosis-related genes in HEI-OC1 cells. Conclusion Using next generation sequencing, our transcriptomic analysis revealed the differences of gene expression pattern with age in the cochlea of C57BL/6 mice. Our study also revealed multiple immune and inflammatory transcriptomic changes during cochlear aging and provides new insights into the molecular mechanisms underlying cochlear inflammation in AHL.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis highlights cochlear inflammation associated with age-related hearing loss in C57BL/6 mice using next generation sequencing

Xiong

Liu

et al. 2020

PeerJ

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“…PRRs recognize pathogen-associated molecular patterns (PAMPs), conserved structures commonly identified among different microorganisms, as well as damage-associated molecular patterns (DAMPS), molecules shed by injured cells. Currently identified classes of PRR families comprise the Tolllike receptors (TLRs) and C-type lectin receptors (CLRs), the Retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) and the nucleotide-binding oligomerization domain (NOD)-Leucine Rich Repeats (LRR)-containing receptors (NLRs), and secreted proteins such as complement proteins (25,26). TLRs are composed of an extracellular and cytoplasmic domain that belongs to a type I transmembrane receptor and recognize TLR ligands through the extracellular domain.…”

Section: Tlrs and Its Signaling Pathwaysmentioning

confidence: 99%

“…Complements belong to the pattern recognition receptors in the innate immune system and involved in recognition and clearance of pathogens, damaged tissues, aggregated proteins, and toxic wastes (165,166). Additionally, complement proteins have been implicated in diverse processes during brain development, aging and neurological diseases (26). Virtually all complement components are locally expressed in the brain and microglia express almost all classical complement components and their receptors including C1qR, CR3, C3aR, and C5aR (167,168).…”

Section: Complement In Aging Brainmentioning

confidence: 99%

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

2020

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Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.

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“…Over the past several years, there has been explosive growth in both academic and commercial programs aimed at developing complement inhibitory drugs, with many anti-complement therapeutics now in various stages of clinical trials. Considering the evidence that complement plays key roles in driving multiple CNS pathologies [reviewed in (22,177,(341)(342)(343)], diseases of the CNS would appear to be an attractive and viable target indication for the next generation of complement therapeutics.…”

Section: Summary and Discussionmentioning

confidence: 99%

Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here?

et al. 2020

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Neurological disorders are major contributors to death and disability worldwide. The pathology of injuries and disease processes includes a cascade of events that often involve molecular and cellular components of the immune system and their interaction with cells and structures within the central nervous system. Because of this, there has been great interest in developing neuroprotective therapeutic approaches that target neuroinflammatory pathways. Several neuroprotective anti-inflammatory agents have been investigated in clinical trials for a variety of neurological diseases and injuries, but to date the results from the great majority of these trials has been disappointing. There nevertheless remains great interest in the development of neuroprotective strategies in this arena. With this in mind, the complement system is being increasingly discussed as an attractive therapeutic target for treating brain injury and neurodegenerative conditions, due to emerging data supporting a pivotal role for complement in promoting multiple downstream activities that promote neuroinflammation and degeneration. As we move forward in testing additional neuroprotective and immune-modulating agents, we believe it will be useful to review past trials and discuss potential factors that may have contributed to failure, which will assist with future agent selection and trial design, including for complement inhibitors. In this context, we also discuss inhibition of the complement system as a potential neuroprotective strategy for neuropathologies of the central nervous system.

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Complement dysregulation in the central nervous system during development and disease

Cited by 82 publications

References 185 publications

Transcriptomic analysis highlights cochlear inflammation associated with age-related hearing loss in C57BL/6 mice using next generation sequencing

Transcriptomic analysis highlights cochlear inflammation associated with age-related hearing loss in C57BL/6 mice using next generation sequencing

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here?

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