The complement activation product C3a is often described as a proinflammatory mediator, alongside its downstream cousin, C5a. However, emerging studies show that C3a has several anti-inflammatory ...facets in vivo. For example, in the acute inflammatory response, C3a acts in direct opposition to C5a, through preventing the accumulation of neutrophils in inflamed tissues by independently regulating their mobilization. This acute, protective, and opposing activity of C3a to C5a is also illustrated in models of septicemia. In this article, we reinvestigate the discovery and original classification of C3a as a proinflammatory mediator and highlight the emerging studies demonstrating anti-inflammatory effects for C3a in the immune response. It is our hope that this review illuminates these apparently contradictory roles for C3a and challenges the general dogma surrounding C3a, which, historically, has ubiquitously been described as a proinflammatory mediator. In light of this, we urge investigators to use "inflammatory modulator" as the descriptor for C3a.
Coronavirus disease of 2019 (COVID-19) is a highly contagious respiratory infection that is caused by the severe acute respiratory syndrome coronavirus 2. Although most people are immunocompetent to ...the virus, a small group fail to mount an effective antiviral response and develop chronic infections that trigger hyperinflammation. This results in major complications, including acute respiratory distress syndrome, disseminated intravascular coagulation, and multiorgan failure, which all carry poor prognoses. Emerging evidence suggests that the complement system plays a key role in this inflammatory reaction. Indeed, patients with severe COVID-19 show prominent complement activation in their lung, skin, and sera, and those individuals who were treated with complement inhibitors all recovered with no adverse reactions. These and other studies hint at complement's therapeutic potential in these sequalae, and thus, to support drug development, in this review, we provide a summary of COVID-19 and review complement's role in COVID-19 acute respiratory distress syndrome and coagulopathy.
•Complement proteins play essential roles in brain development.•Complement signalling can both protect against and aggravate neurological disease.•Complement dysregulation contributes to ...neurodevelopment and neurodegenerative disorders.
The complement cascade is an important arm of the immune system that plays a key role in protecting the central nervous system (CNS) from infection. Recently, it has also become clear that complement proteins have fundamental roles in the developing and aging CNS that are distinct from their roles in immunity. During neurodevelopment, complement signalling is involved in diverse processes including neural tube closure, neural progenitor proliferation and differentiation, neuronal migration, and synaptic pruning. In acute neurotrauma and ischamic brain injury, complement drives inflammation and neuronal death, but also neuroprotection and regeneration. In diseases of the aging CNS including dementias and motor neuron disease, chronic complement activation is associated with glial activation, and synapse and neuron loss. Proper regulation of complement is thus essential to allow for an appropriately developed CNS and prevention of excessive damage following neurotrauma or during neurodegeneration. This review provides a comprehensive overview of the evidence for functional roles of complement in brain formation, and its dysregulation during acute and chronic disease. We also provide working models for how complement can lead to neurodevelopmental disorders such as schizophrenia and autism, and either protect, or propagate neurodegenerative diseases including Alzheimer’s disease and amyotrophic lateral sclerosis.
Complement activation generates the core effector protein C5a, a potent immune molecule that is linked to multiple inflammatory diseases. Two C5a receptors, C5aR1 (C5aR, CD88) and C5aR2 (C5L2, ...GPR77), mediate the biological activities of C5a. Although C5aR1 has broadly acknowledged proinflammatory roles, C5aR2 remains at the center of controversy, with existing findings supporting both immune-activating and immune-dampening functions. Recent progress has been made toward resolving these issues. Instead of being a pure recycler and sequester of C5a, C5aR2 is capable of mediating its own set of signaling events and through these events exerting significant immunomodulatory effects not only toward C5aR1 but also other pattern recognition receptors and innate immune systems, such as NLRP3 inflammasomes. This review highlights the existing knowns and unknowns concerning C5aR2 and provides a timely update on recent breakthroughs which are expected to have a substantial impact on future fundamental and translational C5aR2 research.
•Complement has critical functional roles in embryonic brain development.•C1, C4, C2, C3 and CR3 are critical in synaptic refinement during brain maturation.•Complement activation contributes to ...excessive synaptic pruning in CNS disorders.•Determination of the molecular triggers of complement involvement will direct the pharmacologic development of interventions for currently intractable disorders of the CNS.
While the mechanisms underlying the functions of the complement system in the central nervous system (CNS) and systemically, namely opsonization, chemotaxis, membrane lysis, and regulation of inflammation are the same, the plethora of functions that complement orchestrates in the central nervous system (CNS) is complex. Strictly controlled expression of complement effector molecules, regulators and receptors across the gamut of life stages (embryogenesis, development and maturation, aging and disease) dictate fascinating contributions for this ancient system. Furthermore, it is becoming apparent that complement functions differ widely across distinct brain regions. This review provides a comprehensive overview of the newly identified roles for complement in the brain, including its roles in CNS development and function, during aging and in the processes of neurodegeneration. The diversity and selectively of beneficial and detrimental activities of complement, while challenging, should lead to precision targeting of specific components to provide disease modifying treatments for devastating psychiatric and neurodegenerative disorders that are still without effective treatment.
Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize ...tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions.
The complement system is a collection of soluble and membrane‐bound proteins that together act as a powerful amplifier of the innate and adaptive immune systems. Although its role in infection is ...well established, complement is becoming increasingly recognized as a key contributor to sterile inflammation, a chronic inflammatory process often associated with noncommunicable diseases. In this context, damaged tissues release danger signals and trigger complement, which acts on a range of leukocytes to augment and bridge the innate and adaptive immune systems. Given the detrimental effect of chronic inflammation, the complement system is therefore well placed as an anti‐inflammatory drug target. In this review, we provide a general outline of the sterile activators, effectors, and targets of the complement system and a series of examples (i.e., hypertension, cancer, allograft transplant rejection, and neuroinflammation) that highlight complement's ability to bridge the 2 arms of the immune system.
Complement is a key actor at the innate and adaptive interface and, with a host of noncanonical capabilities, is an important determinant of sterile inflammation.
The complement activation fragment C5a is a potent proinflammatory mediator that is increasingly recognized as an immune modulator. C5a acts through two C5a receptors, C5aR1 (C5aR, CD88) and C5aR2 ...(C5L2, GPR77), to powerfully modify multiple aspects of immune cell function. Although C5aR1 is generally acknowledged to be proinflammatory and immune-activating, the potential roles played by C5aR2 remain poorly defined. Despite studies demonstrating C5aR2 can modulate C5aR1 in human cells, it is not yet known whether C5aR2 functionality is limited to, or requires, C5aR1 activation or influences immune cells more broadly. The present study, therefore, aimed to characterize the roles of C5aR2 on the signaling and function of primary human monocyte-derived macrophages, using a C5aR2 agonist (Ac-RHYPYWR-OH; P32) to selectively activate the receptor. We found that although C5aR2 activation with P32 by itself was devoid of any detectable MAPK signaling activities, C5aR2 agonism significantly dampened C5aR1-, C3aR-, and chemokine-like receptor 1 (CMKLR1)-mediated ERK signaling and altered intracellular calcium mobilization mediated by these receptors. Functionally, selective C5aR2 activation also downregulated cytokine production triggered by various TLRs (TLR2, TLR3, TLR4, and TLR7), C-type lectin receptors (Dectin-1, Dectin-2, and Mincle), and the cytosolic DNA sensor stimulator of IFN genes (STING). Surprisingly, activity at the C-type lectin receptors was particularly powerful, with C5aR2 activation reducing Mincle-mediated IL-6 and TNF-α generation by 80-90%. In sum, this study demonstrates that C5aR2 possesses pleiotropic functions in primary human macrophages, highlighting the role of C5aR2 as a powerful regulator of innate immune function.
The current pandemic of coronavirus disease (COVID-19) caused by SARS-CoV-2 is a significant global health challenge. A recent study by Carvelli and colleagues now demonstrates the involvement of ...complement C5a and its receptor C5aR1 in disease progression and suggests that blockade of the C5a-C5aR1 axis may represent a potential therapeutic strategy against COVID-19.
Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as β‐amyloid and α‐synuclein trigger ...microglial NLRP3 activation, leading to caspase‐1 activation and IL‐1β secretion. Both caspase‐1 and IL‐1β contribute to disease progression in the mouse SOD1G93A model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1G93A mice microglia do not express NLRP3, and SOD1G93A protein generated IL‐1β in microglia independent to NLRP3. Here, we demonstrate using Nlrp3‐GFP gene knock‐in mice that microglia express NLRP3 in SOD1G93A mice. We show that both aggregated and soluble SOD1G93A activates inflammasome in primary mouse microglia leading caspase‐1 and IL‐1β cleavage, ASC speck formation, and the secretion of IL‐1β in a dose‐ and time‐dependent manner. Importantly, SOD1G93A was unable to induce IL‐1β secretion from microglia deficient for Nlrp3, or pretreated with the specific NLRP3 inhibitor MCC950, confirming NLRP3 as the key inflammasome complex mediating SOD1‐induced microglial IL‐1β secretion. Microglial NLRP3 upregulation was also observed in the TDP‐43Q331K ALS mouse model, and TDP‐43 wild‐type and mutant proteins could also activate microglial inflammasomes in a NLRP3‐dependent manner. Mechanistically, we identified the generation of reactive oxygen species and ATP as key events required for SOD1G93A‐mediated NLRP3 activation. Taken together, our data demonstrate that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NLRP3 inflammasome. NLRP3 inhibition may therefore be a potential therapeutic approach to arrest microglial neuroinflammation and ALS disease progression.
Main points
NLRP3 is upregulated and expressed in microglia in ALS mouse models.
SOD1 and TDP‐43 proteins activate NLRP3‐dependent microglial inflammasomes to generate IL‐1β.
ROS and ATP generation are crucial for ALS protein inflammasome activation.
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