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bioRxiv · 10.1101/2024.12.16.628705

FABP5 in Skin Macrophages Mediates Saturated Fat-Induced IL-1β Signaling in Obesity-Associated Psoriasis Development

Yu, J.·Hao, J.·Yorek, M. S.·Jiang, X.·Avellino, A.·Liu, S.·Han, X.·Shilyansky, J.·Wang, Z.·Jabbari, A.·Li, B.
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Abstract

High fat diet (HFD)-induced obesity increases the risk and severity of psoriasis. However, the immunoregulatory effects of different HFD-induced obesity on psoriasis pathogenesis remains poorly understood. Here, mimicking human dietary fat profiles, four HFDs - saturated, monounsaturated, omega-6 and omega-3 fats - were designed and used to induce obesity in mice. Despite comparable obesity levels across groups, only the saturated HFD exacerbated imiquimod (IMQ)-induced psoriasis. This exacerbation correlated with elevated levels of IL-1{beta}-producing macrophages, IL-17A-producing {gamma}{delta} T cells, and neutrophils within psoriatic lesions. Mechanistically, saturated fatty acids (FAs) promoted IL-1{beta}/IL-17 signaling via fatty acid-binding protein 5 (FABP5)-mediated mitochondrial FA oxidation and extracellular ATP release in skin macrophages. Deletion of FABP5, either globally or specifically in macrophages, attenuated IL-1{beta}/IL-17A signaling and alleviated IMQ-induced psoriasis. These findings identify FABP5 as a key mediator of saturated HFD-driven psoriasis via the IL-1{beta}/IL-17 axis, offering insights into the interplay between dietary fats, obesity and psoriasis. HighlightsO_LISaturated, but not unsaturated, high-fat diets (HFDs) drive the development of obesity-associated psoriasis. C_LIO_LISaturated fats enhance IL-1{beta}/IL-17 signaling in psoriatic skin. C_LIO_LIFABP5 mediates saturated fat-induced IL-1{beta} signaling by promoting ATP production and release. C_LIO_LIDeletion of FABP5 in macrophages alleviates the development of saturated HFD-associated psoriasis. C_LI Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/628705v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@93fedaorg.highwire.dtl.DTLVardef@409fa2org.highwire.dtl.DTLVardef@b08362org.highwire.dtl.DTLVardef@81abcc_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Yu, J., Hao, J., Yorek, M. S., Jiang, X., Avellino, A., Liu, S., Han, X., Shilyansky, J., Wang, Z., Jabbari, A., Li, B.. 2024-12-20. FABP5 in Skin Macrophages Mediates Saturated Fat-Induced IL-1β Signaling in Obesity-Associated Psoriasis Development. https://doi.org/10.1101/2024.12.16.628705

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