The classical liver-derived and serum-effective complement system is well appreciated as a key mediator of host protection
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.
Summary
The complement system represents an evolutionary old and critical component of innate immunity where it forms the first line of defense against invading pathogens. Originally described as a ...heat‐labile fraction of the serum responsible for the opsonization and subsequent lytic killing of bacteria, work over the last century firmly established complement as a key mediator of the general inflammatory response but also as an acknowledged vital bridge between innate and adaptive immunity. However, recent studies particularly spanning the last decade have provided new insights into the novel modes and locations of complement activation and highlighted unexpected additional biological functions for this ancient system, for example, in regulating basic processes of the cell. In this review, we will cover the current knowledge about complement's established and novel roles in innate and adaptive immunity with a focus on the functional differences between serum circulating and intracellularly active complement and will describe and discuss the newly discovered cross‐talks of complement with other cell effector systems particularly during T‐cell induction and contraction.
Complement activation generates the core effector protein C5a, a potent immune molecule that is linked to multiple inflammatory diseases. Two C5a receptors, C5aR1 (C5aR, CD88) and C5aR2 (C5L2, ...GPR77), mediate the biological activities of C5a. Although C5aR1 has broadly acknowledged proinflammatory roles, C5aR2 remains at the center of controversy, with existing findings supporting both immune-activating and immune-dampening functions. Recent progress has been made toward resolving these issues. Instead of being a pure recycler and sequester of C5a, C5aR2 is capable of mediating its own set of signaling events and through these events exerting significant immunomodulatory effects not only toward C5aR1 but also other pattern recognition receptors and innate immune systems, such as NLRP3 inflammasomes. This review highlights the existing knowns and unknowns concerning C5aR2 and provides a timely update on recent breakthroughs which are expected to have a substantial impact on future fundamental and translational C5aR2 research.
CD46: The ‘multitasker’ of complement proteins Yamamoto, Hidekazu; Fara, Antonella Francesca; Dasgupta, Prokar ...
The international journal of biochemistry & cell biology,
12/2013, Letnik:
45, Številka:
12
Journal Article
Recenzirano
Complement is undeniably quintessential for innate immunity by detecting and eliminating infectious microorganisms. Recent work, however, highlights an equally profound impact of complement on the ...induction and regulation of a wide range of immune cells. In particular, the complement regulator CD46 emerges as a key sensor of immune activation and a vital modulator of adaptive immunity. In this review, we summarize the current knowledge of CD46-mediated signalling events and their functional consequences on immune-competent cells with a specific focus on those in CD4+ T cells. We will also discuss the promises and challenges that potential therapeutic modulation of CD46 may hold and pose.
In 2014, specific recommendations for complement nomenclature were presented by the complement field. There remained some unresolved designations and new areas of ambiguity, and here we propose ...solutions to resolve these remaining issues. To enable rapid understanding of the intricate complement system and facilitate therapeutic development and application, a uniform nomenclature for cleavage fragments, pattern recognition molecules (PRMs) and enzymes of the lectin pathway and regulatory proteins of the complement system are proposed, and a standardization of language to designate different activation states of complement components is recommended.
Complement: you gutsy thing Kemper, Claudia
Trends in immunology,
April 2024, 2024-Apr, 2024-04-00, 20240401, Letnik:
45, Številka:
4
Journal Article
Recenzirano
Complement, traditionally perceived as a liver-derived and plasma-operative guardian against bloodborne pathogens, is increasingly recognized as a local and central player in tissue immunity. Two ...recent studies, by Xu et al. and Wu et al., validate this concept in the mouse gut, where extrahepatic, intestine-produced, and/or operative C3 protects against enteric infections.
Complement, traditionally perceived as a liver-derived and plasma-operative guardian against bloodborne pathogens, is increasingly recognized as a local and central player in tissue immunity. Two recent studies, by Xu et al. and Wu et al., validate this concept in the mouse gut, where extrahepatic, intestine-produced, and/or operative C3 protects against enteric infections.
Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction ...of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.
Complement is an innate immune system that is a first line of defense against pathogens and facilitates elimination of apoptotic and injured cells. During complement activation, the complement ...convertases are assembled on target surfaces and initiate their proteolytic activities, a process that marks targets for phagocytosis and/or lysis. The complement alternative activation pathway has been implicated in a number of autoimmune conditions including arthritis and age-related macular degeneration. Properdin, a plasma component that is also released by activated neutrophils, is critical in the stabilization of alternative pathway convertases. Recently, it has been shown that properdin is also a pattern-recognition molecule that binds to certain microbial surfaces, apoptotic cells, and necrotic cells. Once bound to a surface, properdin can direct convertase formation and target uptake. New studies are now focusing on a role for properdin in inflammatory and autoimmune diseases. This review examines the new properdin findings and their implications.
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