Aggregated Low-Density Lipoprotein (agLDL) Triggers Inflammatory Responses in Macrophages through Toll-Like Receptor 4 (TLR4)
- 1Ottawa Hospital Research Institute
Abstract
Atherosclerosis is a chronic inflammatory disease primarily initiated by the sub-endothelial retention and modification of low-density lipoproteins (LDL), such as oxidation and aggregation. While oxidized LDL (oxLDL) exists in atherosclerotic lesions, aggregated lipoproteins are also prominent. Aggregated LDL (agLDL), for instance, is viewed as a passive substrate for macrophages to uptake and form foam cells. Recent studies show that agLDL, through toll-like receptor 4 (TLR4), induces formation of lysosomal synapses, which drive agLDL degradation by macrophages, a process described as "digestive exophagy". As TLR4 is one of the pattern-recognition receptors for inflammatory responses in macrophages, we postulated that agLDL could initiate macrophage inflammation along with lipoprotein degradation/internalization, thereby contributing to a low degree of chronic inflammation in atherosclerosis. Here, we demonstrate that agLDL directly activates the canonical NF-{kappa}B signaling pathway and triggers a pro-inflammatory transcriptional program through TLR4, which closely resembles classical lipopolysaccharide (LPS)-mediated TLR4 activation. In addition, agLDL also activates TLR4 to generate inflammatory macrophages that recruit immune cells, a key process in the development of atherosclerotic lesions. Our findings therefore support a novel dual functionality of agLDL: a lipid donor and an inflammatory agonist. This establishes the agLDL-TLR4-NF-{kappa}B axis as a direct link between LDL aggregation in the intima and the initiation of sterile vascular inflammation. It also strengthens the understanding of the role of digestive exophagy with new mechanistic details.
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BibTeX
@misc{zha2026aggregated,
title = {{Aggregated Low-Density Lipoprotein (agLDL) Triggers Inflammatory Responses in Macrophages through Toll-Like Receptor 4 (TLR4)}},
author = {X. Zha and S. Kadri and Z. Salloum and J. Chen and C.-I. J. Ma and D. Zhang and T. Lagace and F. R. Maxfield},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754244},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754244v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Aggregated Low-Density Lipoprotein (agLDL) Triggers Inflammatory Responses in Macrophages through Toll-Like Receptor 4 (TLR4)
AU - X. Zha
AU - S. Kadri
AU - Z. Salloum
AU - J. Chen
AU - C.-I. J. Ma
AU - D. Zhang
AU - T. Lagace
AU - F. R. Maxfield
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754244
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.754244v1
AB - Atherosclerosis is a chronic inflammatory disease primarily initiated by the sub-endothelial retention and modification of low-density lipoproteins (LDL), such as oxidation and aggregation. While oxidized LDL (oxLDL) exists in atherosclerotic lesions, aggregated lipoproteins are also prominent. Aggregated LDL (agLDL), for instance, is viewed as a passive substrate for macrophages to uptake and form foam cells. Recent studies show that agLDL, through toll-like receptor 4 (TLR4), induces formation of lysosomal synapses, which drive agLDL degradation by macrophages, a process described as "digestive exophagy". As TLR4 is one of the pattern-recognition receptors for inflammatory responses in macrophages, we postulated that agLDL could initiate macrophage inflammation along with lipoprotein degradation/internalization, thereby contributing to a low degree of chronic inflammation in atherosclerosis. Here, we demonstrate that agLDL directly activates the canonical NF-{kappa}B signaling pathway and triggers a pro-inflammatory transcriptional program through TLR4, which closely resembles classical lipopolysaccharide (LPS)-mediated TLR4 activation. In addition, agLDL also activates TLR4 to generate inflammatory macrophages that recruit immune cells, a key process in the development of atherosclerotic lesions. Our findings therefore support a novel dual functionality of agLDL: a lipid donor and an inflammatory agonist. This establishes the agLDL-TLR4-NF-{kappa}B axis as a direct link between LDL aggregation in the intima and the initiation of sterile vascular inflammation. It also strengthens the understanding of the role of digestive exophagy with new mechanistic details.
ER -