Local release of properdin in the cellular microenvironment: role in pattern recognition and amplification of the alternative pathway of complement

Abstract

Properdin, the only positive regulatory protein of the complement system, acts as both a stabilizer of the alternative pathway (AP) convertases and as a selective pattern recognition molecule of certain microorganisms and host cells (i.e., apoptotic/necrotic cells) by serving as a platform for de novo C3b,Bb assembly. Properdin, a highly positively charged protein, normally exists as cyclic dimers (P(2)), trimers (P(3)), and tetramers (P(4)) of head-to-tail associations of monomeric 53 kDa subunits. While most complement proteins are produced mainly in the liver, properdin is synthesized primarily by various cell types, including neutrophils, monocytes, primary T cells, and shear-stressed endothelial cells resulting in properdin serum levels of 4-25 μg/ml. Multiple inflammatory agonists stimulate the release of properdin from stimulated leukocytes into the cellular microenvironment. Concentrated, focused increases in properdin levels may lead to stabilization and initiation of AP convertases, thus greatly amplifying the complement response to a local stimulus. This review highlights current knowledge related to these properties and discusses the implications of properdin production in a pro-inflammatory microenvironment.

Keywords: alternative pathway; complement system; inflammation; pattern recognition; properdin.

FIGURE 1

Release of properdin in the local microenvironment. Properdin (P) released by immune cells may directly bind to surfaces (pathogens and cells) and promote AP complement activation. Properdin may recruit C3b or C3(H₂O) to form a C3 convertase and further promote C3b deposition on surfaces (P-mediated complement activation). Sources of C3b may be derived from C3 convertases of the alternative pathway (AP), lectin (LP), or classical pathways (CP). C3(H₂O) derived from “tick over” C3 hydrolysis may also bind to cell-bound properdin, forming a C3(H₂O),Bb convertase on the cell. In addition, properdin can bind to C3b on surfaces and recruit additional C3b and factor B, generating new convertases. Properdin that does not encounter a nearby cell surface may lose the ability to bind to surfaces directly soon after it is in contact with blood, therefore preventing unwanted properdin-mediated complement damage in surrounding areas while keeping the conventional function of stabilizing the C3 and C5 convertases of the AP. Properdin-mediated complement activation may participate in opsonization, MAC deposition, and C3a and C5a release, which are important processes in inflammatory immune responses. Finally, locally released properdin may carry out functions that are independent from complement activation/amplification. For simplicity, the orange triangle represents a properdin trimer.