Secreted phospholipase PLA2G12A-driven lysophospholipid signaling via lipolytic modification of extracellular vesicles facilitates pathogenic Th17 differentiation
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Abstract
Lipogenesis-driven metabolic flux is crucial for differentiation of pathogenic Th17 cells. Although our previous CRISPR-based screening identified PLA2G12A as a key player in this process, it has remained obscure how this secreted phospholipase A 2 isoform controls Th17 differentiation. Here we show that global, T cell-specific, or fibroblast-specific deletion of PLA2G12A prevents Th17 differentiation and associated diseases including psoriasis and arthritis. PLA2G12A acts on Th17-derived extracellular vesicles (EVs) to produce lysophospholipids including the RORγt activator 1-oleoyl-lysophosphatidylethanolamine. These lysophospholipids are further converted by autotaxin to lysophosphatidic acid (LPA), which assists Th17 differentiation mainly via LPA 2 receptor. Moreover, PLA2G12A promotes the secretion and uptake of EVs by Th17 cells and alters their cargo contents. Defective Th17 differentiation by PLA2G12A deficiency is rescued by supplementation with PLA2G12A-modified EVs. Importantly, a PLA2G12A-blocking antibody prevents Th17 differentiation and ameliorates psoriasis and arthritis models. Thus, targeting the PLA2G12A-EV-lysophospholipid axis may be useful for treatment of Th17-related diseases.
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aken together, these findings373suggest that LPA2 likely acts as a main LPA receptor that assists Th17 differentiation374downstream of PLA2G12A,
Is LPA2 also expressed in gamma delta T cells? Or is the increase in this cell population driven by another PLA2G12A-related mechanism?
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Collectively,232these results suggest that PLA2G12A secreted from Th17 cells critically contributes to233psoriasis-like pathology and that PLA2G12A secreted from fibroblasts also has a234supporting role possibly through its paracrine action on T cells
Given that only a portion of psoriasis and RA patients respond to anti-IL-17 therapy, do you think PLA2G12A-directed interventions might work on any non-responders due to the fact that it acts upstream of Th17s? Have you tested the impact of PLA2G12A in disease models that are not known to be driven by IL-17?
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n contrast, PLA2G12A deletion affected the differentiation of165non-pathogenic Th17 cells by IL-6 and TGF-b only minimally (Figure 1J)
How are you determining that the cells in Figure 1J are non-pathogenic Th17s?
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