Complement in metabolic disease: metaflammation and a two-edged sword

Abstract

We are currently experiencing an enduring global epidemic of obesity and diabetes. It is now understood that chronic low-grade tissue inflammation plays an important role in metabolic disease, brought upon by increased uptake of a so-called Western diet, and a more sedentary lifestyle. Many evolutionarily conserved links exist between metabolism and the immune system, and an imbalance in this system induced by chronic over-nutrition has been termed 'metaflammation'. The complement system is an important and evolutionarily ancient part of innate immunity, but recent work has revealed that complement not only is involved in the recognition of pathogens and induction of inflammation, but also plays important roles in cellular and tissue homeostasis. Complement can therefore contribute both positively and negatively to metabolic control, depending on the nature and anatomical site of its activity. This review will therefore focus on the interactions of complement with mechanisms and tissues relevant for metabolic control, obesity and diabetes.

Keywords: Adipocyte; C3; C4BP; CD59; Complement; Diabetes; Inflammation; Insulin; Obesity.

Fig. 1

Pathways of complement activation. A The classical and lectin pathways are activated by the PRRs, C1Q and MBL/ficolins respectively, which recognise PAMPs and DAMPS such as bound antibodies, dead cells and foreign or altered carbohydrates. PRR-associated proteases cleave C2 and C4, which form the C3 convertase, and subsequently cleave C3 into C3b and the anaphylatoxin C3a. C3b itself associates with C4bC2b to form the C5 convertase, which cleaves C5 into the potent anaphylatoxin C5a, and C5b. C5b then associates with complement components 6-9. Poly-C9 forms a membrane-breaching pore that can directly lyse gram-negative bacteria. B The alternative pathway is initiated by spontaneous hydrolysis of C3 to C3H₂O, to which FB can bind. Subsequent conformational changes allow serum protease FD cleave FB to Bb, and C3H₂OBb is the initial alternative pathway C3 convertase. FB also forms a convertase with subsequent C3b products, causing amplification unless regulated by FH. Incorporation of C3b into the C3 convertase allows cleavage of C5, ultimately leading to MAC formation. The alternative pathway is also involved in amplification of the classical and lectin pathways. Previously, C2b was referred to as C2a (2). For further details, see text

Fig. 2

Interactions of complement with metabolic tissues. Serum complement proteins are derived mainly from the liver with the exception of FD, which is expressed primarily in adipocytes and is altered in obesity. Local C3 expression is also found at various anatomical sites. In particular, C3 is highly expressed in human islets. Both circulating levels of C3 and local islet C3 expression are upregulated during T2D. Notably, C3a has been shown to have direct effects on both adipocytes and β-cells, while intracellular isoforms of both C3 and CD59 play homeostatic roles in β-cell survival and function