Complement Has Brains—Do Intracellular Complement and Immunometabolism Cooperate in Tissue Homeostasis and Behavior?

Abstract

The classical liver-derived and serum-effective complement system is well appreciated as a key mediator of host protection via instruction of innate and adaptive immunity. However, recent studies have discovered an intracellularly active complement system, the complosome, which has emerged as a central regulator of the core metabolic pathways fueling human immune cell activity. Induction of expression of components of the complosome, particularly complement component C3, during transmigration from the circulation into peripheral tissues is a defining characteristic of monocytes and T cells in tissues. Intracellular complement activity is required to induce metabolic reprogramming of immune cells, including increased glycolytic flux and OXPHOS, which drive the production of the pro-inflammatory cytokine IFN-γ. Consequently, reduced complosome activity translates into defects in normal monocyte activation, faulty Th1 and cytotoxic T lymphocyte responses and loss of protective tissue immunity. Intriguingly, neurological research has identified an unexpected connection between the physiological presence of innate and adaptive immune cells and certain cytokines, including IFN-γ, in and around the brain and normal brain function. In this opinion piece, we will first review the current state of research regarding complement driven metabolic reprogramming in the context of immune cell tissue entry and residency. We will then discuss how published work on the role of IFN-γ and T cells in the brain support a hypothesis that an evolutionarily conserved cooperation between the complosome, cell metabolism and IFN-γ regulates organismal behavior, as well as immunity.

Role of Complement in Regulating Inflammation Processes in Renal and Prostate Cancers

“…In the non-canonical pathway, several proteases, such as plasmin, can cleave C5, independently of convertase formation. An intracellular cleavage of C3 by cathepsin L also occurs independently of the cascade [8,9]. Indeed, Complosome, the intracellular complement, has been investigated mainly in human CD4 + T cells and correlated to homeostatic cell survival.…”

Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship

“…Finally, recent breakthrough research revealed that not only PPRs but also certain ComC proteins and receptors are expressed intracellularly in T lymphocytes, regulate several aspects of their metabolism, and play an important role in maintaining the functional robustness of these cells. The presence of functional autocrine components of the ComC inside T cells has been described as the “complosome” [ 15 – 18 ]. This finding changed our view of ComC-mediated regulation of immune responses.…”

“…Thus, we will focus in this perspective review on the critical role of innate immunity as an orchestrator of HSPC trafficking. We will also discuss the role of intracellular complement (the complosome), which was initially identified in lymphocytes [ 15 – 18 ] and recent evidence shows is also present in HSPCs [ 8 ]. This evidence sheds new light on intracrine complement involvement in regulating the metabolism and proliferation of HSPCs.…”

“…Another receptor, CD46 (also known as complement regulatory protein or membrane cofactor protein), which is expressed by human cells and is also an inhibitory complement receptor [ 43 ]. Interestingly, this receptor, which will be discussed further, has another function in complosome-mediated effects on hematopoiesis [ 15 – 18 ]. It is important to remember that all these receptors are expressed not only on the surfaces of innate immune cells but also on HSPCs to protect them from hyperactivated ComC products acting outside the hormetic zone.…”

Sublytic membrane attack complex drives glycolysis and mitochondrial dysfunction with inflammatory consequences in human monocyte-derived macrophages

“…Most recently, complement was found to drive inflammatory priming and metabolic reprogramming of synovial fibroblasts (Friscic, Bottcher et al 2021). In addition, it is emerging that complement acts a global immunometabolic regulator, especially in the brain (McDonald, McCombe et al 2020, Kunz andKemper 2021). McDonald et al propose that complement causes a metabolic switch to lipid consumption in amyotrophic lateral sclerosis (ALS), which has broad implications for the field of immunometabolism.…”