Heterocomplexes of Mannose-binding Lectin and the Pentraxins PTX3 or Serum Amyloid P Component Trigger Cross-activation of the Complement System

Abstract

The long pentraxin 3 (PTX3), serum amyloid P component (SAP), and C-reactive protein belong to the pentraxin family of pattern recognition molecules involved in tissue homeostasis and innate immunity. They interact with C1q from the classical complement pathway. Whether this also occurs via the analogous mannose-binding lectin (MBL) from the lectin complement pathway is unknown. Thus, we investigated the possible interaction between MBL and the pentraxins. We report that MBL bound PTX3 and SAP partly via its collagen-like domain but not C-reactive protein. MBL-PTX3 complex formation resulted in recruitment of C1q, but this was not seen for the MBL-SAP complex. However, both MBL-PTX3 and MBL-SAP complexes enhanced C4 and C3 deposition and opsonophagocytosis of Candida albicans by polymorphonuclear leukocytes. Interaction between MBL and PTX3 led to communication between the lectin and classical complement pathways via recruitment of C1q, whereas SAP-enhanced complement activation occurs via a hitherto unknown mechanism. Taken together, MBL-pentraxin heterocomplexes trigger cross-activation of the complement system.

M-Ficolin Interacts with the Long Pentraxin PTX3: A Novel Case of Cross-Talk between Soluble Pattern-Recognition Molecules

“…The molecular and functional characterization of the PTX3-Mficolin interaction described in this study lends further support to the integrated view of humoral innate immunity that emerged recently, according to which different pattern-recognition receptors collaborate in the activation and regulation of protective immune responses (3,(28)(29)(30). Cross talks between members of the defense collagens and pentraxins families are expected to broaden the individual recognition spectrum of these receptors for endogenous and exogenous danger signals and provide synergy in antimicrobial defense and/or maintenance of immune tolerance.…”

“…With respect to the lectin complement pathway, CRP and PTX3 were shown to collaborate with L-ficolin for pathogen recognition and amplification of complement activation (10,28,29). Interaction between MBL and PTX3 was also recently reported to amplify complement activation through recruitment of C1q (30). However, direct ficolin-dependent activation of the lectin pathway by pentraxins has not been described so far (10,28,29).…”

Soluble Collectin-12 (CL-12) Is a Pattern Recognition Molecule Initiating Complement Activation via the Alternative Pathway

“…Complement C4b deposition was determined as previously described (7). In brief, A. fumigatus were incubated with rCL-12R&D (5 mg/ml) before addition of serum MBL2 (10%) as a complement source in the presence of TBS/Ca 2+ .…”

“…However, LP activation is primarily induced by collagen-like sPRMs, such as mannose-binding lectin (MBL) and the ficolins (5). It has also been shown that the CP and LP could be cross-activated through formation of heterocomplexes among PTX3, C1q, and the ficolins, as well as MBL (6,7). In contrast, the AP does not require Abs or sPRMs for its initiation, and it is often referred to as spontaneous and nondiscriminatory because it does not differentiate between self and nonself.…”

Ficolin-1–PTX3 Complex Formation Promotes Clearance of Altered Self-Cells and Modulates IL-8 Production

“…Proteins were separated by 3-8% or 4-12% SDS-PAGE gel under reducing or nonreducing conditions according to the method of Laemmli (35) and visualized by immunoblotting or Coomassie brilliant blue, as described previously (29,36).…”