Complement is an essential component of the intrinsic immune system, comprising a set of serum-functioning proteasome cascade pathways that play a crucial role in clearing invading pathogens and senescent dying cells. Protease cleavage of core complement C3 serves as the convergence point of activation for three separate complement pathways. The classical complement pathway and the lectin complement pathway are activated by antibody-mediated antigen binding and glycan recognition on the microbial surface, respectively, while the complement bypass pathway is self-activating. Complement pathway activation is precisely and systematically regulated to maintain homeostasis and protect host tissues from aberrant damage.
Although most complement originates from the liver, some complement is produced outside the liver, such as in immune cells. In humans, after bone marrow transplantation, only 5% of C3 in the circulatory system originates from the liver. Immune cell-derived complement receptor activation is not dependent on serum ligands but mediates cellular immunity through paracrine or autocrine pathways, including the activation of lymphocyte function and regulation of invading pathogens and apoptotic cells. In addition, C3 and C5 cleavage products are biologically active within the cell and can regulate basic intracellular activities. Based on these phenomena and facts, it can be established that hepatic complement produced in situ can lead to sustained infiltration of lymphocytes, potentially associated with chronic inflammatory dysfunctions associated with aging.
Atherosclerosis is a type of lipid-induced chronic inflammatory disease. In the atherosclerotic pathologic process, monocyte-derived macrophages play a central role in the maladaptive inflammatory response. While serum-derived complement was previously believed to drive atherosclerosis pathology, recent research involving single-cell sequencing of atherosclerotic plaques suggests that these plaques contain biologically active complement, primarily sourced from macrophage subsets at the lesion site. Although it is well established that atherosclerotic plaques contain complement proteins, and these proteins have both protective and detrimental effects on the body, the exact function of the complement system in the formation of atherosclerotic foci and in spontaneous cellular responses remains unknown.
Recently, Christoph J. Binder’s research group from the Medical University of Vienna, Austria, published an article in Immunity entitled Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis, providing insights into these issues.
Complement factor H (CFH), primarily originating in the liver, is a central regulator of the complement bypass pathway and the most abundant complement inhibitory factor in the cytosol. By accelerating C3 convertase degradation, CFH can inhibit C3 cleavage in the liquid phase and also inhibit C3 function by binding to glycosaminoglycans and malondialdehyde epitopes on the cell surface. Thus, CFH-deficient mice result in uncontrollable systemic complement activation due to continued C3 production and accumulation. Human individuals harboring CFH mutations also develop severe chronic inflammatory diseases such as membranoproliferative glomerulonephritis and age-related macular degeneration.
The authors focused on the role of CFH in the pathologic process of atherosclerosis. Using a mouse model of atherosclerosis, the authors found that CFH deficiency effectively limits C3-dependent plaque necrosis. Knockdown of CFH in monocyte-derived inflammatory macrophages resulted in spontaneous uncontrolled C3 uptake by the cells without downstream C5 activation.
Among lymphocytes, only monocytes and macrophages express CFH, and its content increases with inflammation, synchronized with the abnormal accumulation of intracellular C3. In addition, macrophage-derived CFH effectively reduces inflammation, and CFH deficiency in the livers of atherosclerosis model mice significantly promotes cytosolic burial at lesions and reduces plaque volume. Of particular note, the authors determined that monocyte-derived inflammatory macrophages in human atherosclerotic plaques express both C3 and CFH.
In summary, the authors’ work suggests a new pathway for cell-autonomous regulation of the complement system: complement factor CFH can regulate macrophage intracellular C3 levels. This study identifies a key role for this complement regulatory mechanism in the pathologic progression of inflammatory diseases.
Reference:
1. Kiss, Máté G., et al. “Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis.” Immunity 56.8 (2023): 1809-1824.