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

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.

Keywords: Brain injury; Complement; Intervention; Intracerebral hemorrhage.

Figure 1.. Complement cascade schematic illustration.

Complement activation through three proximal pathways promotes inflammation, phagocytosis, and creation of the membrane attack complex (MAC). The early complement products, C3a and C5a, act as anaphylatoxins and chemotaxins; together they recruit granulocytes and promote degranulation; attract phagocytic cells, inducing pro-inflammatory polarization; induce reactive astrocytes; and stimulate smooth muscle, increase vascular permeability and promote vasodilation.

Figure 2.. Complement mediated erythrolysis exacerbates brain injury.

MAC lyse and rupture erythrocytes, contributing to the release of hemoglobin, peroxiredoxin 2 (Prx2), and carbonic anhydrase 1 (CA1). Prx2 and CA1 can trigger neuroinflammation and cause brain damage directly. Hemoglobin binding to haptoglobin is taken up into macrophages/microglia or neurons through CD163 mediated transport. Within the cells, hemoglobin is degraded into heme, which is then metabolized into carbon monoxide, biliverdin and Fe²⁺ by heme-oxygenase (HO)-1 in macrophages/microglia or HO-2 in neurons. Ferritin is present within macrophages/microglia to bind iron but is not present in neurons, making the latter sensitive to iron overload.

Figure 3.. Complement mediated opsonophagocytosis.

Stressed neurons can express C1q, which tags them along with cellular debris for clearance by phagocytes. Apoptotic or necrotic cells generate C3b/iC3b, which interacts with CR1 or CR3 on phagocytes, facilitating the removal of these injured cells. Erythrocytes express CR1 on their surface, which can interact with macrophage expressing CR1 or CR3 via C3b opsonized particles. C3b can form an immune complex by binding with natural occurring antibodies (NAbs), which are resistant to complement inhibitory proteins thereby enhancing erythrophagocytosis.