The role of the anaphylatoxins in health and disease

Abstract

The anaphylatoxins (AT) C3a, C5a and C5a-desArg are generally considered pro-inflammatory polypeptides generated after proteolytic cleavage of C3 and C5 in response to complement activation. Their well appreciated effector functions include chemotaxis and activation of granulocytes, mast cells and macrophages. Recent evidence suggests that ATs are also generated locally within tissues by pathogen-, cell-, or contact system-derived proteases. This local generation of ATs is important for their pleiotropic biologic effects beyond inflammation. The ATs exert most of the biologic activities through ligation of three cognate receptors, i.e. the C3a receptor, the C5a receptor and the C5a receptor-like, C5L2. Here, we will discuss recent findings suggesting that ATs regulate cell apoptosis, lipid metabolism as well as innate and adaptive immune responses through their impact on antigen-presenting cells and T cells. As we will outline, such regulatory functions of ATs and their receptors play important roles in the pathogenesis of allergy, autoimmunity, neurodegenerative diseases, cancer and infections with intracellular pathogens.

Human Skin Mast Cells Express Complement Factors C3 and C5

“…Local production of C3 by dendritic cells in mice, for example, promotes Th1 development (41,47). C3a can amplify pathologic process by increasing vasopermeability, contracting bronchial smooth muscle, stimulating dendritic cells to modulate T cell activation, or activating mast cells and basophils, of likely importance in allergic disorders such as asthma and in autoimmune urticaria (88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98). Furthermore, C3adesArg, a metabolite of C3a, serves as an adipokine associated with obesity, type II diabetes, and coronary artery disease (99).…”

C5aR-dependent cell activation by physiological concentrations of C5a-desArg: Insights from a novel label-free cellular assay

“…Anaphylatoxin-induced inflammatory responses play a crucial role in many physiological and pathophysiological processes, and their therapeutic modulation has moved into the spotlight of complement-related drug discovery efforts (2,25). Yet, while the triggering of cell responses by anaphylatoxin receptors is well appreciated, their quantitation so far have mostly been assessed indirectly by means of calcium release, cell degranulation, oxygen burst, cytokine production, and chemotaxis (5).…”

“…Anaphylatoxins exert their biological functions via the G protein-coupled receptors (GPCR) C3a receptor (C3aR) and C5a receptor (C5aR; CD88), which are present at the surface of several types of myeloid cells as well as tissue cells (2). Carboxypeptidases present in the serum and tissues quickly degrade C3a and C5a by removing their C-terminal arginine (Arg) residue, producing the so-called C3a desArg and C5a desArg anaphylatoxin fragments (3).…”

“…Nearly 12 years after its discovery, C5L2 is still considered an enigmatic molecule. Divergent roles have been suggested for this receptor, ranging from decoy and regulatory to anti-and pro-inflammatory (2), and it is clear that further studies are required to fully elucidate its participation in the modulation of cellular responses. The most recent report addressing molecular mechanisms has indicated that C5L2 is predominantly intracellular in human neutrophils and that it acts by negatively modulating C5a-induced C5aR signaling through the activation of the β-arrestin signaling pathway (12).…”

Molecular cloning and expression analysis of Pleurodeles waltl complement component C3 under normal physiological conditions and environmental stresses

“…C3a and C5a are anaphylatoxins that exert a plethora of pro-inflammatory and immunoregulatory functions (Guo and Ward, 2005). In addition to their pro-inflammatory properties, these molecules regulate antigen-presenting cell functions and adaptive immune responses (Klos et al, 2009). Indeed, C3a and C5a have been shown to modulate the expression levels of MHC class II and costimulatory molecules on dendritic cells (Strainic et al, 2008;Weaver et al, 2010).…”