Complement’s hidden arsenal: New insights and novel functions inside the cell

Abstract

A key component of both innate and adaptive immunity, new understandings of the complement system are expanding its roles beyond that traditionally appreciated. Evidence is accumulating that complement has an intracellular arsenal of components that provide not only immune defense, but also assist in key interactions for host cell functions. Although early work has primarily centered on T cells, the intracellular complement system likely functions in many if not most cells of the body. Some of these functions may trace their origins to the primitive complement system that began as a primeval form of C3 likely tasked for protection from intracellular pathogen invasion. This later expanded to include extracellular defense as C3 became a secreted protein to patrol the vasculature. Other components were added to the growing system including regulators to protect host cells from the indiscriminate effects of this potent system. Contemporary cells may retain some of these vestigial remnants. We now know that a) C3 serves as a damage-associated molecular pattern (in particular by coating pathogens that translocate into cells), b) most cells store C3 and recycle C3(H2O) for immediate use, and c) C3 assists in cellular survival and metabolic reprogramming. Other components also are part of this hidden arsenal including C5, properdin, factors H and B, and complement receptors. Importantly, better definition of the intracellular complement system may translate into new target discovery to assist in creating the next generation of complement therapeutics.

The Neonatal Fc Receptor and Complement Fixation Facilitate Prophylactic Vaccine-Mediated Humoral Protection against Viral Infection in the Ocular Mucosa

“…It remains unclear why cornea-infiltrating leukocytes express much lower levels of FcRn than is observed in circulating leukocytes (Fig. 8I, J); it tempting to speculate that leukocytes store antibody in circulation via FcRn-mediated retention for discharge upon activation and extravasation into inflamed tissues as they are proposed to do with soluble complement components (74). …”

Novel mechanisms and functions of complement

“…The activation of complement anaphylatoxins may not necessarily occur in the extracellular milieu and recent studies have substantiated the existence of intracellular stores of complement components and receptors ( e.g ., anaphylatoxin receptors and their ligands; C3b, factor B, factor H), which perform novel homeostatic and surveillance functions within human T cells 7,13,14 . A cell-intrinsic and functionally active complement system was anticipated more than 30 years ago by pioneering studies showing that human lymphocytes synthesize various complement components, regulators, and receptors 15,16 .…”

“…Complement components can be secreted locally by tissue-resident and infiltrating cells, while emerging evidence suggests the existence of an intracellular complement system with novel homeostatic and immune functions 2 . New insights into the mechanisms and locations of complement activation have revealed a new layer of complexity in the biology of complement and its impact on health and disease 7,8 . When dysregulated or overactivated due to host genetic or microbial virulence factors, complement can turn from a homeostatic to a pathological effector that drives various inflammatory disorders and cancer, which reflect the multifaceted nature of complement interactions 3,9 .…”

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

“…Locally produced complements are known to play an important role in tissue homeostasis, and thus, dysfunction or dysregulation of the system may contribute to various diseases. Recent studies have shown that the complement system can also be activated inside the cell, and intracellular complement activation is known to be involved in many important cellular functions, including intracellular pathogen recognition/elimination, cytokine production, and metabolism (Arbore et al, ; Kolev & Kemper, ; Liszewski et al, ).…”