Canonical and non?canonical functions of the complement system in health and disease

This article is part of a themed issue on Canonical and non-canonical functions the complement system in health disease. To view other articles this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc The forms network more than 30 soluble proteins cell-bound receptors that perform multiple sensor effector as innate immune system. It well appreciated protects host from hostile microbial environment through opsonization direct lysis microorganisms. Progress made at beginning 21st century showed it contributes to integrity tissues organs by effectively eliminating altered or dead cells. Moreover, original are limited serum has been continuously expanded over last two decades. Further, structure interaction many with extracellular intracellular have molecularly defined (Forneris et al., 2012). In addition known canonical activation pathways, mechanisms described, which lead cleavage factors not only circulation but also named “complosome” (Arbore 2017; Kolev 2014). fact, studies indicate bidirectional interactions immunity systems regulates responses acquired (Hajishengallis 2017). Interestingly, directly intervenes differentiation cells cell metabolism, thus contributing significantly homeostasis (West 2020). From an evolutionary point view, these surprising given around for 1.2 billion years, making one oldest parts our Complement may even evolved initial purpose distinct protection against pathogens rather intrinsic cellular stress. We will discuss how taking closer look into evolution key components functional connection between metabolism ‘predictable’ give clues discovery additional roles basic processes. pathways novel uncovered during past decade make ever important field research hot topic immunology particular light ongoing coronavirus pandemic. increasing number clinical conditions involve pathological contribution spurred renewed interest therapeutic interventions, order modulate defence pathway (Pandey Based findings, pharmaceutical industry identified system, specifically anaphylatoxins their receptors, potential promising targets inflammatory diseases (Ricklin 2018). 2007, antibody C5 (eculizumab) was approved FDA treatment paroxysmal nocturnal haemoglobinuria (PNH) later atypical haemolytic syndrome (aHUS) autoimmune neuromuscular disorders (Legendre 2013). More 20 candidate drugs, targeting various stages cascade currently being evaluated trials, agents preclinical development. For example, ChemoCentryx reported successful completion Phase III trial showing orally administered C5a1 receptor antagonist (avacopan) superior corticosteroid antineutrophil cytoplasmic (ANCA)-associated vasculitis (Jayne 2021) replace therapy future (Warrington, 2021). led renaissance complement-targeted drug discovery. Besides, indications inhibition rapidly complexity. divided parts. First, highlights recent discoveries, changed dramatically such metabolic complement. second new several major scientific medical community including infections, hypertension, thrombosis trauma. contributions different authors summarised Figure 1. first part, Merle al. (2021) integrins orchestrate metabolisms immunity. addition, Rahman describe role regulation mitochondrial activity. King recently discovered C3 autophagy pancreatic autophagy. Hevey (2021), Skerka round up describing carbohydrate sensing endothelial ApoE. With broadening span activities, makes sense revisit topics its pathogens. issue, Jodele Köhl highlight infection highly pathogenic coronaviruses focus genetics target SARS-CoV-2 infection. development arterial hypertension relatively area discussed Wenzel (2021). Huber-Lang Portilla Xavier Rawish summarize progress understanding emerging thrombosis, kidney disease These observations sparked motivated scientists re-evaluate activity—now fresh eye functions—in diseases, where plays complement-driven molecular remain be defined. paralleled efforts further exploring activities normal physiology formerly associated activation. hope selected spur readers help uncover secrets still holds us.