The Lectin Pathway of the Complement System—Activation, Regulation, Disease Connections and Interplay with Other (Proteolytic) Systems

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1566 - 1566

Published: Jan. 26, 2024

The complement system is the other major proteolytic cascade in blood of vertebrates besides coagulation–fibrinolytic system. Among three main activation routes complement, lectin pathway (LP) has been discovered latest, and it still subject intense research. Mannose-binding (MBL), collectins, ficolins are collectively termed as pattern recognition molecules (PRMs) LP, they responsible for targeting LP to molecular patterns, e.g., on bacteria. MBL-associated serine proteases (MASPs) effectors, while proteins (MAps) have regulatory functions. Two protease components, MASP-1 MASP-2, trigger activation, third component, MASP-3, involved function alternative (AP) complement. Besides their functions within system, certain components secondary (“moonlighting”) functions, embryonic development. They also contribute coagulation, some might tumor suppressing roles. Uncontrolled can progression many diseases (e.g., stroke, kidney diseases, thrombotic complications, COVID-19). In most cases, implicated. this review, we summarize history pathway, introduce describe its regulation, roles cascade, connections direct cellular effects. Special emphasis placed disease non-canonical components.

Language: Английский

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Beyond the Norm: The emerging interplay of complement system and extracellular matrix in the tumor microenvironment

Seminars in Immunology, Journal Year: 2025, Volume and Issue: 77, P. 101929 - 101929

Published: Jan. 9, 2025

Language: Английский

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Inflammation in the Peripheral Nervous System after Injury

Biomedicines, Journal Year: 2024, Volume and Issue: 12(6), P. 1256 - 1256

Published: June 5, 2024

Nerve injury is a common condition that occurs as result of trauma, iatrogenic injury, or long-lasting stimulation. Unlike the central nervous system (CNS), peripheral (PNS) has strong capacity for self-repair and regeneration. Peripheral nerve results in degeneration distal axons myelin sheaths. Macrophages Schwann cells (SCs) can phagocytose damaged cells. Wallerian (WD) makes whole axon structure degenerate, creating favorable regenerative environment new axons. After macrophages, neutrophils other are mobilized recruited to site necrotic debris. Pro-inflammatory anti-inflammatory factors involved inflammatory response provide microenvironment regeneration regulate effects inflammation on body through relevant signaling pathways. Previously, was thought be detrimental body, but further research shown appropriate promotes regeneration, formation. On contrary, excessive cause tissue damage pathological changes, even lead neurological diseases. Therefore, after various interact with cytokines chemokines promote repair by inhibiting negative harnessing positive specific ways at times. Understanding interaction between neuroinflammation provides several therapeutic ideas improve

Language: Английский

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Complement and the hallmarks of cancer

Seminars in Immunology, Journal Year: 2025, Volume and Issue: 78, P. 101950 - 101950

Published: April 4, 2025

The hallmarks of cancer are a set traits that normal cells acquire during their transformation into malignancy. Among the biological processes influencing these hallmarks, innate immune complement system plays critical role. It can operate canonically-in blood and tissues-via phagocytosis, inflammation, complement-dependent cytotoxicity, similar to its roles against invading pathogens. Additionally, it functions non-canonically by modulating behavior within tumor microenvironment intracellular landscape which regulates cell fate. These mechanisms contribute complex context-dependent in both growth antitumor immunity, shaped characteristics dynamic microenvironment. This review analyses multifaceted interplay between proteins positioning this as target therapy.

Language: Английский

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Ketamine’s mechanism of action with an emphasis on neuroimmune regulation: can the complement system complement ketamine’s antidepressant effects?

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(9), P. 2849 - 2858

Published: April 4, 2024

Language: Английский

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The complement system in neurodegenerative diseases

Clinical Science, Journal Year: 2024, Volume and Issue: 138(6), P. 387 - 412

Published: March 1, 2024

Abstract Complement is an important component of innate immune defence against pathogens and crucial for efficient complex disposal. These core protective activities are dependent in large part on properly regulated complement-mediated inflammation. Dysregulated complement activation, often driven by persistence activating triggers, a cause pathological inflammation numerous diseases, including neurological diseases. Increasingly, this has become apparent not only well-recognized neuroinflammatory diseases like multiple sclerosis but also neurodegenerative neuropsychiatric where was previously either ignored or dismissed as secondary event. There now rapidly growing body evidence implicating that cannot be comprehensively addressed brief review. Here, we will focus the ‘classical’ such Alzheimer’s disease Parkinson’s disease, two other neurodegeneration neglected feature implicated, namely, schizophrenia, neurodevelopmental disorder with many mechanistic features neurodegeneration, sclerosis, demyelinating major progressive decline. We discuss driver pathology these diverse address briefly potential pitfalls anti-complement drug therapy

Language: Английский

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C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer’s disease mouse model

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 15, 2024

Alzheimer's disease (AD) is the leading cause of dementia in older adults, and need for effective, sustainable therapeutic targets imperative. The complement pathway has been proposed as a target. C5aR1 inhibition reduces plaque load, gliosis, memory deficits animal models, however, cellular bases underlying this neuroprotection were unclear. Here, we show that antagonist PMX205 improves outcomes Arctic48 mouse model AD. A combination single cell nucleus RNA-seq analysis hippocampi derived from males females identified neurotoxic disease-associated microglia clusters Arctic mice are C5aR1-dependent, while microglial genes associated with synapse organization transmission learning overrepresented PMX205-treated mice. also reduced astrocyte gene expression, but protective responses to injury unchanged. promoted mRNA-predicted signaling pathways between brain types growth repair, suppressing inflammatory pathways. Finally, although hippocampal load was unaffected, prevented short-term female In conclusion, prevents cognitive loss, limits detrimental glial polarization permitting neuroprotective responses, well leaving most functions intact, making antagonism an attractive strategy

Language: Английский

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The schizophrenia risk gene C4 induces pathological synaptic loss by impairing AMPAR trafficking

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

Neuroimmune interactions play a significant role in regulating synaptic plasticity both the healthy and diseased brain. The complement pathway, an extracellular proteolytic cascade, exemplifies these interactions. Its activation triggers microglia-dependent elimination via receptor 3 (CR3). Current models of pathological activity brain propose that accelerated loss resulting from overexpression C4 (C4-OE), gene associated with schizophrenia, follows this pathway. Here, we report C4-mediated cortical hypoconnectivity is CR3-independent. Instead, C4-OE impaired GluR1 trafficking through intracellular mechanism involving endosomal protein SNX27, loss. Moreover, circuit alterations prefrontal cortex, region neuropsychiatric disorders, were rescued by increasing neuronal levels which identify as interacting partner neuroimmune protein. Our results link excessive to endo-lysosomal pathway altering plasticity.

Language: Английский

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Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 118, P. 355 - 363

Published: March 12, 2024

Complement is dysregulated in the brain Alzheimer's Disease and mouse models of disease. Each complement derived effectors, opsonins, anaphylatoxins membrane attack complex (MAC), have been implicated as drivers disease but their relative contributions remain unclarified. Here we focussed on MAC, a lytic pro-inflammatory effector, AppNL−G−F amyloidopathy model. To test role back-crossed to generate mice deficient C7, an essential MAC component. C7 deficiency ablated formation, reduced synapse loss amyloid load improved cognition compared complement-sufficient at 8–10 months age. Adding back caused increased formation acute synapses C7-deficient mice. explore whether was viable therapeutic target, C7-blocking monoclonal antibody administered systemically for one month aged 8–9 months. Treatment deposition, density cognitive performance isotype control-treated The findings implicate driver pathology highlight potential inhibition level therapy

Language: Английский

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Neuroinflammatory Proteins in Huntington’s Disease: Insights into Mechanisms, Diagnosis, and Therapeutic Implications

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(21), P. 11787 - 11787

Published: Nov. 2, 2024

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by CAG tract expansion in the huntingtin gene (

Language: Английский

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