FcRn-mediated antibody recycling drives plaque vulnerability in symptomatic atherosclerosis
S Lin, J Deroissart, Y Yu, S Malin, K Oorni, U Hedin, C Binder, A GisteraAbstract
Background
Atherosclerotic plaques contain low-density lipoproteins (LDL) and antibodies, including those directed against LDL and its apolipoprotein (apo) B100 molecule. Interactions between apoB and antibodies lead to the formation of apoB-immune complexes that can engage Fc receptors on myeloid cells within the plaque. Preliminary evidence suggests that the accumulation of intraplaque antibodies is associated with morphological features characteristic of rupture-prone plaques.
Purpose
To determine how free apoB-specific antibodies and apoB-immune complexes dynamically regulate plaque vulnerability, and to identify the mechanisms controlling the balance between these two immunological states.
Methods
In a cohort of patients with carotid stenosis undergoing endarterectomy, levels of free apoB-specific antibodies and apoB-immune complexes were measured in carotid plaques and peripheral blood using immunoassays. These measures were correlated with patients’ clinical characteristics and manifestations. Hypothesis-driven targets were further validated using single-cell sequencing data from carotid plaques. Mechanistic studies were subsequently performed using myeloid cell lines and ex vivo carotid plaque biopsy specimens.
Results
ApoB-specific antibodies were more abundant in plaques from symptomatic patients, who concurrently exhibited lower levels of apoB-immune complexes. The neonatal Fc receptor (FcRn) was highly expressed by plaque-resident macrophages and mediated antibody recycling by promoting the dissociation of immune complexes into extracellular free antibodies. FcRn expression was found to increase with age and correlated with plaque vulnerability factors, including collagenase expression. In vitro blockade of FcRn in a human myeloid cell line using Rozanolixizumab effectively inhibited FcRn-mediated effects, resulting in reduced conversion of immune complexes into extracellular free antibodies. FcRn inhibition also significantly decreased cellular production of the collagenase matrix metalloproteinase-9 (MMP-9), a collagenase strongly associated with plaque rupture. Consistently, ex vivo FcRn blockade in carotid plaque biopsy specimens reduced intraplaque free antibody levels, attenuated proinflammatory effects and showed a decreasing trend in MMP-9 production.
Conclusion
These findings identify FcRn as a key regulator of macrophage-driven plaque vulnerability, revealing a mechanistic association between antibody recycling and plaque destabilization. Therapeutic inhibition of FcRn with the clinically available agent Rozanolixizumab may represent a novel strategy to stabilize atherosclerotic plaques and reduce the risk of acute ischemic events.