Role of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 in Inflammation and Pathogen-Associated Interactions

Abstract

Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is known as a major receptor for oxidized low-density lipoproteins (oxLDL) and plays a significant role in the genesis of atherosclerosis. Recent research has shown its involvement in cancer, ischemic stroke, and diabetes. LOX-1 is a C-type lectin receptor and is involved in the activation of immune cells and inflammatory processes. It may further interact with pathogens, suggesting a role in infections or the host's response.

Summary: This review compiles the current knowledge of potential implications of LOX-1 in inflammatory processes and in host-pathogen interactions with a particular emphasis on its regulatory role in immune responses. Also discussed are genomic and structural variations found in LOX-1 homologs across different species as well as potential involvements of LOX-1 in inflammatory processes from the angle of different cell types and organ-specific interactions.

Key messages: The results presented reveal both similar and different structures in human and murine LOX-1 and provide clues as to the possible origins of different modes of interaction. These descriptions raise concerns about the suitability, particularly of mouse models, that are often used in the analysis of its functionality in humans. Further research should also aim to better understand the mostly unknown binding and interaction mechanisms between LOX-1 and different pathogens. This pursuit will not only enhance our understanding of LOX-1 involvement in inflammatory processes but also identify potential targets for immunomodulatory approaches.

Keywords: C-type lectin-like receptors; Infection response; Inflammation; LOX-1; Lectin-like oxidized low-density lipoprotein receptor-1; Oxidized low-density lipoprotein.

Fig. 1.

Schematic overview of LOX-1-regulated pathways in cardiovascular diseases. Stated are agents upregulating LOX-1 (top of the figure) as well as factors being upregulated (green arrows) or downregulated (red arrows) upon LOX-1 activation and the resulting physiological effects (in bold). Created with BioRender.com.

Fig. 2.

Schematic illustration of the LOX-1 receptor. In the cytoplasmatic membrane, LOX-1 exists as disulfide-linked homodimer. It consists of a CTL domain (CTLD), a neck domain (neck), a transmembrane domain (TM), and a cytoplasmic domain (CT) with an amino acid tail. The disulfide bridge stabilizing the human LOX-1 dimer is marked in orange. Created with BioRender.com.

Fig. 3.

Schematic representation of the human OLR1 gene and the LOX-1 primary protein structure. a Shown is the gene structure with the promotor region of OLR1 and the CAAT and TATA boxes as well as the position and length of the exons (based on data from Ensembl.org version 108 [31]). b Protein structure of LOX-1 showing the different domains of LOX-1 (colors) and the cysteine 140 location.

Fig. 4.

Comparative analysis of PRR-coding gene homologs across different species. a Analysis of the LOX-1 gene homologs and the CTLD-region showing the similarity (in percentage) to the human LOX-1 sequence (based on coding sequence analysis on Ensembl.org version 108 [31]). b Comparison of homologs from different PRR families (NLR, TLR, RLR, CTLR) between human and mouse. Shown are the similarity values for each of the receptor-coding genes (based on data from Ensembl.org version 108 [31]).

Fig. 5.

Phylogenetic tree for OLR1 across different species. The left side shows the maximum likelihood phylogenetic tree generated by the Gene Orthology/Paralogy prediction method pipeline within Ensembl.org version 108 [31]. The right side of the figure shows the genetic organization of OLR1 and the alignments between phylogenetic groups. It depicts a transcribed structure in the middle of the OLR1 gene, which is only present in mice, rats, and partially in Cricetidae, representing a genomic difference to the gene structure found in humans and other species.

Fig. 6.

Model of human and murine LOX-1 protein. The left side shows a model of human and murine LOX-1 dimer, generated with Alphafold [37]. The alignment of the human and mouse LOX-1 protein sequence is depicted on the right side. The DDL motif is marked in purple.

Fig. 7.

Cytoplasmic domains of selected C-type lectins of the Dectin-1 and Dectin-2 clusters. The CTLRs show different cytoplasmic signaling motifs. The main ones are ITAM, ITIM, and hemITAM. The signaling motif of LOX-1, on the other hand, is not yet known. The C-type lectins marked with * do only bind ligands in a dimeric form, while for (*), a dimeric as well as a monomeric form represent active C-type lectins and are therefore able to bind ligands in both forms. Created with BioRender.com. The figure is based on [18, 19], and the dimerization information is based on [, –44].

Fig. 8.

Schematic representation of human LOX-1 splice variants LOXIN, sLOX-1, and OLR1D4 and their interactions with LOX-1. Created with BioRender.com, modified from [39].

Fig. 9.

Schematic representation of the LOX-1 mRNA expression in human organs. The expression levels are shown as normalized transcripts per million (nTPM) for all organs with an expression higher than 6 nTPM (as retrieved from RNA-sequencing data in The Human Protein Atlas, proteinatlas.org, version 22.0 [20]). Created with BioRender.com.

Fig. 10.

Summary of the known interactions of LOX-1 with infectious agents (fungi, viruses, and bacteria). Shown are the reported activating particles/pathways (arrows to the receptor) and the known effector mechanisms and induced downstream mediators/proteins (arrows from the receptor). Fungal activators/mechanisms are depicted on a green background, bacterial ones on an orange background, and viral proteins on a purple background. Effector molecule functions are color-coded, while frame intensities indicate the consistency of the finding in the literature (number of times reported). Created with BioRender.com.

Fig. 11.

Illustration of possible signaling pathways of LOX-1. Shown are the activation of MAPK-pathways [–131], NF-κB pathways [, –131], Calpain-modulation [129], apoptosis-pathways [129, 132], and others [20, 39, 129, 130], leading to the already known effects of LOX-1: enhancement of macrophage migration, endothelial dysfunction, apoptosis, autophagy, inflammation, VSMC migration, and monocyte infiltration, as described in the literature. It is known that LOX-1 uses ROCK2 and ARHGEF1 for signaling, but the exact mechanisms are unknown. These unknown activation mechanisms are shown in dashed lines. OxLDL is shown as the best known ligand of LOX-1, for LOX-1 activation. Created with BioRender.com.