Pentraxins in Complement Activation and Regulation

Abstract

The complement is the first line of immune defense system involved in elimination of invading pathogens and dying host cells. Its activation is mainly triggered by immune complexes or pattern recognition molecules (PRMs) upon recognition against non-self or altered self-cells, such as C1q, collectins, ficolins, and properdin. Recent findings have interestingly shown that the pentraxins (C-reactive protein, CRP; serum-amyloid P component, SAP; long pentraxin 3, PTX3) are involved in complement activation and amplification via communication with complement initiation PRMs, but also complement regulation via recruitment of complement regulators, for instance C4b binding protein (C4BP) and factor H (fH). This review addresses the potential roles of the pentraxins in the complement system during infection and inflammation, and emphasizes the underlining implications of the pentraxins in the context of complement activation and regulation both under physiological and pathological conditions.

Keywords: CRP; PTX3; SAP; collectin; complement activation; complement regulation; pentraxins; the ficolins.

Figure 1

Classical model of complement activation and regulation. Complement activation occurs typically through three routes. Classical pathway activation is triggered by the C1 complex comprising C1q, C1s, and C1r upon binding to IgM or clusters of IgG against pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) (4). Lectin pathway activation is induced by soluble pattern recognition molecules (PRMs) mannose-binding lectin (MBL) upon binding to PAMPs or DAMPs. It is now apparent that the ficolins (ficolin −1,−2, or−3) or collectins (collectin-10, collectin-11 or a heteromeric complex of collectin-10 and collectin-11) are also involved in lectin pathway activation (–9). Unlike C1q complexed with the serine proteases C1r and C1s, PRMs involving lectin pathway activation are often associated with the mannose-binding lectin-associated serine proteases (MASPs). Upon classical and lectin pathway activation, the serine proteases cleave C4 and C2 to form C3 convertase (C4b·C2a). In contrast, alternative pathway activation occurs by direct tick-over activation of C3 thioester in solution regardless of trigger, and creates its own C3 convertase (C3b·Bb) when activated C3b covalently bind to the target surfaces in contact with factor B (fB) and the enzyme factor D (fD) (10, 11). The alternative C3 convertase is highly stabilized when properdin is associated. With release of anaphylatoxin C3a, surface-bound C3 convertases generate more opsonin C3b, leading to the formation of the classical and lectin pathway C5 convertase (C3b·C4b·C2a) and the alternative C5 convertase (C3b·Bb·C3b). The C5 convertase in turn cleaves C5 into another anaphylatoxin C5a and C5b. Surface-deposited C5b sequentially recruits complement subunits C6, C7, C8, and C9 on target surface and initiates formation of C5b-9 membrane attack complex (MAC) also named the terminal complement complex (TCC) which may lead to target lysis (3, 12). The alternative pathway also serves to amplify classical and lectin pathway activation. Fluid-phase and cell-bound regulators help to modulate complement over-activation; C1 inhibitor (C1-INH) controls the functions of C1r, C1s and MASP-2; C3b and C4b are inactivated by either fluid-phase factor H (fH)/C4b-binding protein (C4BP) or cell-bound complement receptor type 1 (CR1)/CD46 as cofactors for factor I (fI). Fluid-phase fH/C4BP or cell-bound CR1/CD55 regulate convertase activity by disassembly through decay-accelerating activity of the regulators. The formation of MAC is controlled by CD59 (3).

Figure 2

Pentraxins-expanded network of complement activation and regulation. Classical pathway (CP) activation mainly occurs by immune complexes, but also mediated through antibody-like features of the pentraxins in complex with C1q. In addition to the traditional activating fashion as depicted above, lectin pathway (LP) is also indirectly activated by PTX3, CRP, or SAP upon recruitment of MBL or the ficolins. Cross-activation of the CP and LP initiates when heterocomplexes are created on target surfaces between PTX3 (or CRP) and MBL (or ficolin-2) and C1q. Two additional activation pathways emerge to boost complement amplification. The amplification pathways comprise the avenue open to the sequence below: target → PTX3 (or CRP) → ficolin-2/MASPs → C4 → C3 → formation of membrane attach complex (MAC) (amplification 1); target → MBL (or ficolin-2/MASPs) → PTX3 (or CRP) → C1q → C4 → C3 → formation of MAC (amplification 2) (3). Alternative pathway (AP) activation often occurs independently regardless of trigger by spontaneous C3 activation in solution, and rapidly propels nascent C3b binding to nearby target surfaces covalently. In addition, it is hypothesized that surface-bound collectin-12 (CL-12) mediates CP activation by crosstalk with PTX3, CRP or SAP. A recent emerging activation avenue follows relatively specific sequence that involves pattern recognition and opsonization by soluble CL-12 → recruitment of properdin → de novo C3 convertase assembly → C3 amplification loop → generation of downstream effector molecules → induction of immune signaling (28). Despite its diverse avenues, overarching concept of complement activation focuses on sensing and eliminating potential danger signals through immunesurveillance and immune effector mechanisms. The pentraxins recognize major fluid-phase complement regulators, C4BP and fH, resulting in down-regulation of complement-mediated inflammation.