Porphyromonas gingivalis facilitated the foam cell formation via lysosomal integral membrane protein 2 (LIMP2)

Abstract

Objective The involvement of lysosomal integral membrane protein 2 (LIMP2) in cholesterol transport and formation of foam cells under the infection of Porphyromonas gingivalis (P. gingivalis) is yet to be elucidated. The current study verified the role and explored the mechanism of LIMP2 in promoting foam cell formation by P. gingivalis. Background An association between periodontitis and atherosclerosis (AS) has been established. P. gingivalis is a key pathogen of periodontitis that promotes foam cell formation by regulating activities of CD36 scavenger receptors expressed on the macrophages. LIMP2, a member of CD36 superfamily, is involved in cholesterol efflux. However, whether LIMP2 is involved in the formation of foam cells promoted by P. gingivalis remains unclear. Methods The formation of foam cells was examined by Oil Red O staining. The knockdown of limp2 was identified by qRT‐PCR. The accumulation of cholesterol was monitored by Cholesterol Assay Kit. The location of P. gingivalis was visualized by confocal microscopy. Cathepsin L activity was monitored with Magic Red Cathepsin L Assay Kit. The key genes and pathways in P. gingivalis‐infected macrophages were explored by RNA sequencing. The protein level was investigated by Western blotting. Results Porphyromonas gingivalis increases foam cells formation and upregulates the expression of LIMP2 in foam cells. The knockdown of limp2 decreases the number of foam cells and increases cholesterol export, which is related to lysosomal functions. In addition, the interaction between LIMP2 and caveolin‐1(CAV1) might contribute to this process, and NF‐κB and JNK activity is required for increased expression of P. gingivalis‐induced LIMP2. Conclusions This study suggested that LIMP2 is involved in the foam cells formation facilitated by P. gingivalis, which favors a close connection between periodontitis and atherosclerosis (AS).

Bibliometric research on analysis of links between periodontitis and cardiovascular diseases

“…These immune cells, along with Porphyromonas gingivalis -induced inflammation, promote the uptake of modified low-density lipoprotein (LDL) by macrophages, resulting in the formation of foam cells ( 21 , 22 ). P. gingivalis promotes lipid accumulation in macrophages by upregulating CD36 and inhibiting cholesterol efflux from macrophages by promoting lysosomal integral membrane protein 2 ( 23 , 24 ). By interfering with lipid metabolism, P. gingivalis promotes macrophages to covert to foam cells.…”

Gut Microbiota and Cardiovascular Disease: Evidence on the Metabolic and Inflammatory Background of a Complex Relationship

“…Interestingly, P. gingivalis DNA was detected also in atherosclerotic plaques of subjects with periodontitis. Clinical and animal studies have pointed out that P. gingivalis accelerates atherosclerosis [103,104]; the mechanisms can be multiple, and include: (a) intracellular influx of oxidized-LDL and its conversion to cholesterol crystals, via increased expression of CD36 and fatty acid binding protein 4 (FABP4) on macrophages [105,106]; (b) activation of NLRP3 inflammasomes by cholesterol crystals' damage to the phagolysosomes and P. gingivalis-induced production of reactive oxygen species, with consequent activation of the inflammatory cascade [107,108]; (c) downregulation of the cholesterol transporters ATP-binding cassettes (ABCA1) on macrophages, which promotes cholesterol accumulation [109]. The pathogenesis of SLE has been associated with dysbiosis, which is mainly characterized by a lower Firmicutes/Bacteroides ratio and overabundance of Ruminococcus gnavus, Enterococcus gallinarum, Streptococcus anginosus, Streptococcus dispar, Veillonella, and Campylobacter, and contributes to disease development and progression through pro-inflammatory stimulation and production of anti-dsDNA antibodies [110][111][112].…”

Porphyromonas gingivalis regulates atherosclerosis through an immune pathway

“…4.2.4.3 P. gingivalis inhibits lipid efflux from macrophages P. gingivalis LPS promotes lipid accumulation in macrophages by activating the JNK-c-Jun/AP-1 pathway to up-regulate CD36 (lipid uptake) expression, while down-regulating ATP-binding cassette transporterA1 (lipid efflux) expression by enhancing calpain activity (230). Secondly, P. gingivalis may inhibit cholesterol efflux by activating NF-kB and JNK signaling pathways, which in turn upregulates lysosomal integral membrane protein 2 (LIMP2) expression levels in macrophages (242). In addition, P. gingivalis inhibited the activity of cholesterol efflux-related enzymes (ABCG1 and CYP46A1) and promoted lipid accumulation in macrophages by enhancing Ca 2+ signaling and promoting ROS production (243).…”