Novel potential inhibitors of complement system and their roles in complement regulation and beyond
Section snippets
Complement system regulation at a glance
The complement system is an ancient innate immune-surveillance system classically described as providing the first line of defense against pathogens and mediating the clearance of host cells, but more recently has been shown to play an instrumental role in immunological and inflammatory processes during homeostasis (Ricklin et al., 2010, Freeley et al., 2016).
Over 50 serum circulating proteins, cell surface receptors and regulators comprise this large intricate effector system (Fig. 1).
Proteins containing complement control protein domains
One common trait of many well-established complement inhibitors is the presence of multiple, consecutive complement control protein (CCP) domains, alternatively known as short consensus repeats (SCR) or Sushi domains. This trait raised the possibility that further proteins containing several such domains, such as CSMD1 or SUSD4 may regulate complement. In this review, their roles in regulating the complement cascade, as well as in other cellular processes are discussed.
Extracellular matrix proteins as regulators of the complement system
Extracellular matrix (ECM) proteins represent the non-cellular components that surround the cells within all tissues and organs. ECM macromolecules build up a dynamic three-dimensional network around the cells that not only provide them with a structural support but also regulate key cellular processes in physiological and pathological conditions (Fig. 4). The composition of these matrices is organ-specific. However, the major constituents represent two main classes of macromolecules: fibrous
Take home message
Accumulating reports of non-conventional complement inhibitors, with functions related to their complement action or/and independent, are emerging in many physiological and pathological conditions, For example, SUSD and CSMD families are introduced as novel disease biomarkers in cancer, neurodegenerative diseases with potential use in their therapy. Additionally, the net outcome of ECM macromolecules’ effects on complement cascade propagation depends on the delicate balance of ECM composition
Acknowledgments
Our studies in this field were funded by the Swedish Research Council, Cancerfonden, and grants for clinical research (ALF). Dr. Maisem Laabei is kindly acknowledged for critical comments and language correction of this review.
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