The role of complement inhibitors beyond controlling inflammation

Abstract

Abstract. Blom AM (Lund University, Malm€ o, Sweden). The role of complement inhibitors beyond controlling inflammation (Review). J Intern Med 2017; 282: 116-128.The complement system is an arm of innate immunity that aids in the removal of pathogens and dying cells. Due to its harmful, pro-inflammatory potential, complement is controlled by several soluble and membrane-bound inhibitors. This family of complement regulators has been recently extended by the discovery of several new members, and it is becoming apparent that these proteins harbour additional functions. In this review, the current state of knowledge of the physiological functions of four complement regulators will be described: cartilage oligomeric matrix protein (COMP), CUB and sushi multiple domains 1 (CSMD1), sushi domain-containing protein 4 (SUSD4) and CD59. Complement activation is involved in both the development of and defence against cancer. COMP expression is pro-oncogenic, whereas CSMD1 and SUSD4 act as tumour suppressors. These effects may be related in part to the complex influence of complement on cancer but also depend on unrelated functions such as the protection of cells from endoplasmic reticulum stress conveyed by intracellular COMP. CD59 is the main inhibitor of the membrane attack complex, and its deficiency leads to complement attack on erythrocytes and severe haemolytic anaemia, which is now amenable to treatment with an inhibitor of C5 cleavage. Unexpectedly, the intracellular pool of CD59 is crucial for insulin secretion from pancreatic b-cells. This finding is one of several relating to the intracellular functions of complement proteins, which until recently were only considered to be present in the extracellular space. Understanding the alternative functions of complement inhibitors may unravel unexpected links between complement and other physiological systems, but is also important for better design of therapeutic complement inhibition.

A guiding map for inflammation

“…Receptor antagonists, such as the IL-1R antagonist (IL-1Ra), bind to IL-1R without inducing an intracellular signal and as such inhibiting the biological activity of IL-1α and IL-1β15. Complement inhibitors also modulate inflammation16 and prostaglandins and lipid mediators such as resolvins exert negative feed-back loops by suppressing the transcription and release of cytokines. Acute phase proteins induced during inflammation, such as α-1 antitrypsin (AAT), have broad anti-inflammatory properties17.…”

Bioinformatics Analysis to Screen the Key Prognostic Genes in Tumor Microenvironment of Bladder Cancer

“…As a crucial component of ECM, COMP has the capacity to regulate activation of the complement system and thus innate immunity [37]. In addition, high expression of COMP protects the cells from endoplasmic reticulum (ER) stress, and cells overexpressing the COMP gene undergo a metabolic switch known as the Warburg effect [38,39]. Furthermore, high COMP expression plays a crucial role in regulating cellular metabolism by blocking intracellular Ca 2+ signaling and thus blocking the apoptosis process of the cells [39].…”

Complement system's role in cancer and its therapeutic potential in ovarian cancer

“…78 Downregulation of CSMD1 expression was associated with decreased survival time for breast cancer patients. 78 The tumour suppressor effect of CSMD1 is shown in vitro to be due to decreased proliferation and migration, and enhanced apoptosis. Similar to SUSD4, it is not clear whether the effects are mediated by complement but both cases provide compelling evidence that complement system has intrinsic plasticity.…”

“…Another complement inhibitor, CUB and sushi multiple domains 1 (CSMD1) is highly expressed in human brain and testes. 78 It inhibits all three complement pathways by acting on C3 convertase and enhancing the function of factor I. CSMD1 is shown to be deleted in diverse types of cancer including skin, breast and lung cancers. 78 Downregulation of CSMD1 expression was associated with decreased survival time for breast cancer patients.…”