Complement-Mediated Regulation of Metabolism and Basic Cellular Processes

Abstract

Complement is well appreciated as critical arm of innate immunity. It is required for the removal of invading pathogens and functions by direct pathogen destruction and through the activation of innate and adaptive immune cells. However, complement activation and function is not confined to the extracellular space but also occurs within cells. Recent work indicates that complement activation regulates key metabolic pathways and thus can impact fundamental processes of the cell, such as survival, proliferation, and autophagy. Novel identified functions of complement include a key role in shaping metabolic reprogramming, which underlies T cell effector differentiation, and a role as a nexus for interactions with other effector systems, in particular the inflammasome and Notch transcription factor networks. This review focuses on the contributions of complement to basic processes of the cell, in particular the integration of complement with cellular metabolism, and the potential implications in infection and other disease settings.

Keeping It All Going—Complement Meets Metabolism

“…Importantly, distinct metabolic signatures encompassing metabolic enzymes, nutrient sensor and metabolic checkpoint systems, and epigenetic changes in genes coding for proteins involved in metabolic pathways “accompany” distinct phases of immune responses including the non-activated and/or resting state, the adaption response, and the contraction and memory phases (6, 59, 60). Because T cell development and the respective activation states of T cells (naïve, effector, and memory) can be manipulated and monitored relatively easily in vitro and in vivo , significant progress has been made particularly in understanding how the cell metabolic machinery enables and drives T cell immunity (61).…”

“…However, complement-mediated regulation on metabolism likely occurs in a wide range of cells, clearly engages other (intracellular) effector systems, and impacts on additional cell basic physiological pathways such as cell survival and autophagy. We refer the readers to two recent reviews that cover these important additional subjects in-depth including an outlook into potential novel roles for complement in infection and in diseases with a metabolic “angle” (6, 82). …”

“…In this regard, it is noteworthy that the only cell type in the human body lacking mitochondria are erythrocytes (157) and that erythrocytes are also the only cells devoid of CD46 expression (158). It is generally speculated that the “loss” of CD46 expression by red blood cells is a protective measure against fast spread of measles virus [which uses CD46 as cell entry receptor (6)]. However, there could be an alternative explanation pointing to a novel role for CD46 in cell metabolism: intriguingly, avian erythrocytes contain functional mitochondria (159) and their red blood cells do express the CD46 analog molecules CREG and CREM (160).…”

“…This system not only plays a central role in metabolic diseases (6), it is also entirely thinkable now that complement may directly impact on a process that has been a fundamental interest in human philosophy and medicine alike since centuries—aging. Restriction of caloric intake has long been recognized to extend the life span in several animal species, including humans.…”

“…Activation of these PPR systems not only induces an immediate strong protective effector response by innate immune cells such as neutrophils, monocytes, and natural killer T cells but also leads to the activation and instruction of adaptive immunity (2, 4, 5). Although it has long been appreciated that engagement of PPRs on and/or in cells and subsequent induction of their respective downstream effector pathways is required for the expression and secretion of cytokines, growth factors, cytotoxic molecules, and general activation of immune cells, what has been unexpected is that many of these events are driven by direct impact of PPRs on cell metabolism (6). Specifically, the emerging critical role for the complement system in the regulation of key metabolic pathways of cells has been surprising, as complement is commonly considered a serum-effective system with its functions mostly fully explored.…”