Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Abstract

The complement system is an essential part of innate immunity, typically conferring protection via eliminating pathogens and accumulating debris. However, the defensive function of the complement system can exacerbate immune, inflammatory, and degenerative responses in various pathological conditions. Cumulative evidence indicates that the complement system plays a critical role in the pathogenesis of ischemic brain injury, as the depletion of certain complement components or the inhibition of complement activation could reduce ischemic brain injury. Although multiple candidates modulating or inhibiting complement activation show massive potential for the treatment of ischemic stroke, the clinical availability of complement inhibitors remains limited. The complement system is also involved in neural plasticity and neurogenesis during cerebral ischemia. Thus, unexpected side effects could be induced if the systemic complement system is inhibited. In this review, we highlighted the recent concepts and discoveries of the roles of different kinds of complement components, such as C3a, C5a, and their receptors, in both normal brain physiology and the pathophysiology of brain ischemia. In addition, we comprehensively reviewed the current development of complement-targeted therapy for ischemic stroke and discussed the challenges of bringing these therapies into the clinic. The design of future experiments was also discussed to better characterize the role of complement in both tissue injury and recovery after cerebral ischemia. More studies are needed to elucidate the molecular and cellular mechanisms of how complement components exert their functions in different stages of ischemic stroke to optimize the intervention of targeting the complement system.

Programmed Cell Deaths and Potential Crosstalk With Blood–Brain Barrier Dysfunction After Hemorrhagic Stroke

“…This is due to stimuli, such as neurotoxic factor accumulation and reduced blood flow, which then causes the release of proinflammatory cytokines (Ge et al, 2018;. Among other CNS diseases, such as cerebral ischemia, Alzheimer disease, or multiple sclerosis, the mechanisms of leukocytic infiltration into the brain and the immune response with the complement system have been widely studied (Jiang et al, 2018;Sweeney et al, 2018;Ma et al, 2019;Shen et al, 2019). DL-3-n-Butylphthalide, a synthetic compound that has been approved for the treatment of ischemic stroke in China, has been shown to inhibit neurovascular inflammation via downregulation of intercellular adhesion molecule 1 (ICAM-1; .…”

Characteristics of Biopeptides Released In Silico from Collagens Using Quantitative Parameters

“…The activity of the complement system, involving, e.g., proteolytic enzyme Complement factor B (alternative-complement-pathway C3/C5 convertase; EC 3.4.21.47) is an important part of the innate immunity [72]. However, this system's function can exacerbate immune, inflammatory, and degenerative responses in pathological conditions, e.g., ischemic stroke [72]. Hyperactivation of the complement alternative pathway is associated with genetic and autoimmune diseases [73].…”

Neuroimmune crosstalk and evolving pharmacotherapies in neurodegenerative diseases

“…The complement system plays a significant role in the pathogenesis of ischaemic stroke. 221,222 After an ischaemic attack, the levels of C3a, C4d and soluble C5b-9 in plasma are increased instantly, while the elevation of C5a occurs within 7-14 days. 223,222 The role of C1q, initiator of the classical pathway in the pathogenesis of ischaemic stroke, is quite complex.…”

“…227 Compared with the above two pathways, the alternative pathway has also been reported in ischaemic stroke pathology. 221,222,223 Factor B-deficient mice, when treated with CR2-fH, an alternative pathway inhibitor, show better improvement 24 h post-reperfusion. 228 CR2-fH inhibits the complement activation site by recognizing C3 opsonin.…”