Review article
The role of complement in brain injury following intracerebral hemorrhage: A review

https://doi.org/10.1016/j.expneurol.2021.113654Get rights and content

Abstract

Intracerebral hemorrhage (ICH) is a significant cause of death and disability and current treatment is limited to supportive measures to reduce brain edema and secondary hematoma expansion. Current evidence suggests that the complement cascade is activated early after hemorrhage and contributes to brain edema/injury in multiple ways. The aim of this review is to summarize the most recent literature about the role of the complement cascade after ICH. Primary literature demonstrating complement mediated brain edema and neurologic injury through the membrane attack complex (MAC) as well as C3a and C5a are reviewed. Further, attenuation of brain edema and improved functional outcomes are demonstrated after inhibition of specific components of the complement cascade. Conversely, complement also plays a significant role in neurologic recovery after ICH and in other neurologic disorders. We conclude that the role of complement after ICH is complex. Understanding the role of complement after ICH is essential and may elucidate possible interventions to reduce brain edema and injury.

Introduction

Intracranial hemorrhage can be broken down into intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), subdural/epidural hemorrhage and intraventricular hemorrhage (Naidech, 2011). This review will focus on the role of complement in ICH which accounts for 9–27% (Steiner et al., 2014; Thrift et al., 2001) of all strokes. ICH is a significant cause of death and disability: 30-day mortality is about 50% (Thrift et al., 2001) and at 1 year 75–84% of patients are unable to achieve functional independence (Pinho et al., 2019). Common causes of ICH include hypertension, amyloid angiopathy, and less commonly vascular malformations and coagulopathies (Keep et al., 2012; Steiner et al., 2014). Prognosis depends on the size and location of the hematoma (Xi et al., 2006). Although surgical evacuation has been proposed and trialed against best medical management, it has not shown any significant benefit in patient functional outcome (Hanley et al., 2019; Mendelow et al., 2013). Current evidence-based management of ICH is limited to supportive measures to prevent hematoma expansion and reduce brain edema (Steiner et al., 2014).

Brain injury from ICH is not only caused by mass effect from the hematoma, but also from the neurotoxicity of blood components, and subsequent intracerebral cellular and inflammatory activation (Keep et al., 2012). Disruption of the blood-brain barrier (BBB), activation of microglia/macrophages in the surrounding brain parenchyma, influx of neutrophils and monocytes, cytokine release as well as activation of the complement cascade contribute to brain edema and injury after ICH (Keep et al., 2012; Xi et al., 2006; Ye et al., 2021). These changes are important for the clearance of blood products and cellular debris in the subacute to chronic phase after ICH, but in the acute phase may cause more harm than good (Aronowski and Hall, 2005; Wang and Dore, 2007). There are multiple mechanisms of brain injury following ICH, but they are outside the scope of this review and therefore, specifically, the role of complement in brain injury and edema will be discussed.

This review focuses specifically on the role of complement in brain edema and injury after ICH. The most relevant studies on this topic were identified through MEDLINE (accessed by PubMed on September 30, 2020), using the following terms: ‘complement’ and ‘intracranial hemorrhage/hematoma’, ‘intracerebral hemorrhage/hematoma’, or ‘intraparenchymal hemorrhage/hematoma’. The reference lists of retrieved articles were reviewed to search for additional reports of relevant data. Both preclinical and clinical studies were selected if components of the complement cascade and their associations with ICH were reported.

Section snippets

Complement cascade overview

The complement cascade, involving 30 serum and membrane bound proteins, is part of the innate immune system and contributes to opsonization, cytolysis, and inflammation (Dunkelberger and Song, 2010). Complement has been implicated in a variety of neurologic and non-neurologic diseases (Ducruet et al., 2009). There are three proximal pathways which converge to act on complement component 3 (C3) (Fig. 1). C3 is converted to C3a and C3b by C3 convertase. C3b, along with other factors, assembles C5

Complement in the central nervous system

The BBB is made up of cerebral endothelial cells and their linking tight junctions (Daneman and Prat, 2015). It is regulated by perivascular cells, including pericytes and astrocyte foot processes, to form the neurovascular unit (Luissint et al., 2012). The BBB limits the entry of circulating leukocytes and proteins into the brain (Takeshita and Ransohoff, 2012). Most of the complement cascade proteins are produced in the liver and therefore, with an intact BBB, peripheral complement does not

Complement activation in intracerebral hemorrhage

Complement activation was first demonstrated after ICH in a rat model in 2000. Hua and colleagues demonstrated elevated levels of complement cascade activation and MAC formation in the perihematomal region at 24 and 72 h after hemorrhage, indicating early complement activation. MAC and clusterin were detected in the perihematomal tissue after 3 days (Hua et al., 2000). Since this initial paper, others have similarly demonstrated complement activation after ICH. Elevated levels of C3a and C5a

Effects of age and sex difference on the complement system

Both age and sex are known to have significant impact on the innate immune system (Giefing-Kroll et al., 2015). The complement system is no exception. In a study based on a cohort of healthy Caucasian adults, females were found to have significantly lower alternative pathway activity, while classical pathway and lectin pathway were not different (Gaya da Costa et al., 2018). In addition, aging significantly increased classical and alternative pathway activity, in contrast to lectin pathway

Polymorphisms of complement cascade components in patients with ICH

The role of complement in brain edema and injury has been discussed in this review primarily in the context of animal models, the results of which are summarized in Table 1. In contrast, there are few human studies of complement in ICH. Conclusions about complement cascade in human ICH are therefore drawn from limited data. Genetic variation in the complement pathway and its receptors has been studied in humans. A recent study identified that CR1, which is known as the C3b/C4b receptor, acted

Conclusions

The aim of this review was to summarize and analyze the most recent primary literature about the role of the complement cascade after ICH. ICH is a prevalent disease and the second most common cause of stroke (Thrift et al., 2001). Treatment is limited to medical management to reduce brain edema and risk of secondary hematoma expansion (Hemphill et al., 2015). Inflammation after ICH plays a key role in brain edema formation. It is clear that complement is activated early after hemorrhage and

Funding

YH, RFK and GX were supported by grants NS-091545, NS-090925, NS-096917, NS106746 and NS116786 from the National Institutes of Health (NIH).

Conflict of interests

Katherine Holste, Fan Xia, Hugh J. L. Garton, MD, Shu Wan, Ya Hua, Richard F. Keep, and Guohua Xi declare no conflict of interests.

Acknowledgements

We would like to thank BioRender.com for being an excellent tool in illustration.

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    Katherine Holste and Fan Xia contributed equally to this review.

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