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. 2021 Sep 3;12:707267. doi: 10.3389/fimmu.2021.707267

Figure 8.

Figure 8

Schematic representation of the identified unique metabolites, enrichment pathways, and proposed genes and their roles in the initiation and progression of each periapical lesion. (A) In periapical abscess, the unique metabolic environment stimulates the conversion of leukotriene B4 (LTB4) to 20-HETE and the downregulation of IL-12A. In turn, these upregulate the expression of MMP-9 and VEGF. IL-12A also stimulates the differentiation of naive T cells to T-helper 1 cells and stimulates NK cells and CD8 cytotoxic T lymphocytes. (B) In radicular cyst, IL-12 enhances the effector CD8 T cells and memory CD8 T cells. Released IL-12A inhibits VEGF and MMP-9 and hence reduces angiogenesis, while lipophagy is enhanced in foam macrophages. IL-17A released from T-helper 17 directly enhances bone resorption by stimulating osteoclasts. (C) In periapical granuloma, L-(+)-lactic acid is the main unique metabolite, which polarizes the conversion of T-helper cells to T-helper 17 through the enhancement of transcription factor RORγ which supports the release of IL-17 and may stimulate RXR-VDR and PPAR-α pathways. RXR-VDR inhibits MMP-9 and PPAR-α negatively regulates VEGF and TLR4. Lactic acid also enhances the polarization of macrophages to the anti-inflammatory M2 phenotype while supporting IL-10 responses.