Lectin-like oxidized LDL receptor 1 is involved in CRP-mediated complement activation
Yoshiko Fujita1, Saburo Yamaguchi, Akemi Kakino
1Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Insights
C-reactive protein (CRP) activates the complement system via the lectin-like oxidized LDL receptor 1 (LOX-1) in a calcium-dependent manner. This LOX-1 involvement in CRP-induced complement activation and inflammation was observed in both cell cultures and a rat model.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- C-reactive protein (CRP) is a risk factor for mortality in ischemic heart disease, independent of LDL cholesterol.
- Lectin-like oxidized LDL receptor 1 (LOX-1) is implicated in endothelial dysfunction and myocardial injury.
- Previous work showed CRP increases vascular permeability by binding to LOX-1.
Purpose of the Study:
- To investigate the role of LOX-1 in C-reactive protein (CRP)-induced complement activation.
- To examine this interaction in a hypertensive rat model.
Main Methods:
- Utilized a cultured LOX-1-expressing cell line (hLOX-1-CHO) and native CHO cells.
- Performed complement activation assays with and without C1q depletion.
- Used immobilized recombinant LOX-1 and CRP with serum.
- Administered CRP intradermally to hypertensive rats (SHRSP).
- Assessed complement activation via C3d deposition and leukocyte infiltration.
- Investigated the effect of anti-LOX-1 antibody in vivo.
Main Results:
- CRP induced complement activation in LOX-1-expressing cells but not in native cells.
- C1q depletion abolished CRP-induced complement activation.
- CRP activated the classical complement pathway via LOX-1 in a calcium-dependent manner, with binding influenced by phosphocholine.
- In hypertensive rats, CRP injection led to complement activation and leukocyte infiltration.
- Anti-LOX-1 antibody significantly reduced these effects.
Conclusions:
- Lectin-like oxidized LDL receptor 1 (LOX-1) plays a role in C-reactive protein (CRP)-induced complement activation.
- LOX-1 may direct the localization of CRP-mediated complement activation and subsequent inflammation.
Background:
C-reactive protein (CRP) is purported to be a risk factor that acts independently of LDL cholesterol in predicting all-cause mortality in patients with ischemic heart disease. Lectin-like oxidized LDL receptor 1 (LOX-1) impairs endothelial function and exacerbates myocardial injury. We recently demonstrated that CRP increased vascular permeability through direct binding to LOX-1. Here we examined, using a hypertensive rat model, whether LOX-1 is involved in CRP-induced complement activation.
Methods And Results:
In the cultured LOX-1-expressing cell line hLOX-1-CHO, CRP increased complement activation, but did not do so in native CHO cells. Depleting C1q from serum abolished CRP-induced complement activation. Incubation of CRP with serum on immobilized recombinant LOX-1 similarly showed that CRP activated C1q-requiring classical complement pathway in a LOX-1-dependent manner. Interestingly, the interaction between CRP and LOX-1 was dependent on Ca²⁺ ion and competed with phosphocholine, suggesting that LOX-1 bound to the B-face of CRP with a phosphocholine-binding domain. This was in contrast to Fcγ receptors, to which CRP bound in A-face with complement-binding domain. In vivo, intradermal injection of CRP to hypertensive SHRSP rats induced complement activation detected by C3d deposition and leukocyte infiltration around the injected area. Anti-LOX-1 antibody reduced the extent of complement activation and leukocyte infiltration.
Conclusions:
LOX-1 appears to be involved in CRP-induced complement activation, and thus may serve to locate the site of CRP-induced complement activation and inflammation.
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