Biology subjects

Avellino, A.

Publications and source records attributed to Avellino, A..

3 recordsLinked to original sources

bioRxiv2026

FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Macrophages

Metabolic dysregulation in obesity reshapes immune function, but how lipid signals drive immune suppression remains unclear. Here, we identify a FABP4-PD-L1 axis that links lipid metabolism to immune checkpoint regulation in monocytes and macrophages. Single-cell transcriptomics revealed a distinct FABP4high immunosuppressive macrophage subset enriched under high-fat diet (HFD) conditions, characterized by impaired antigen presentation and elevated PD-L1 expression. Mechanistically, palmitic acid (PA) induces FABP4 and promotes PD-L1 palmitoylation, leading to its stabilization on the cell surface independent of transcriptional regulation. FABP4 is essential for this process, which enables PD-L1 surface stabilization, immunosuppression and mammary tumor progression. In humans, a conserved CD14intCD16 monocyte population exhibits elevated FABP4-PD-L1 signaling and correlates with obesity and invasive breast cancer. These findings establish PD-L1 as a metabolically regulated protein and reveal a mechanism by which lipid excess drives immune evasion, suggesting that targeting FABP4 may enhance responses to immune checkpoint blockade. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/717546v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1fe3f2corg.highwire.dtl.DTLVardef@e587a7org.highwire.dtl.DTLVardef@12d0f75org.highwire.dtl.DTLVardef@151f916_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIFABP4 defines a lipid-responsive, immunosuppressive monocyte/macrophage subset C_LIO_LIFABP4 links lipid sensing to PD-L1 expression in macrophages C_LIO_LIFABP4 enables palmitic acid-dependent PD-L1 palmitoylation and stabilization C_LIO_LIFABP4-PD-L1 signaling correlates with obesity and invasive breast cancer in humans C_LI

immunology↗

bioRxiv2026

Targeting Circulating FABP4 Ameliorates Obesity-Associated Hepatic Steatosis

Obesity is a major driver of hepatic steatosis, yet the molecular link between excess adiposity and hepatocellular lipid accumulation remains incompletely defined. Here, we identify circulating fatty acid-binding protein 4 (FABP4) as a key mediator of adipocyte-hepatocyte lipid crosstalk in obesity. Analyses of human liver specimens and mouse models reveal aberrant accumulation of FABP4 protein--but not transcript--in hepatocytes during steatosis, indicating an extrinsic source. Genetic deletion of FABP4, specifically in adipocytes, protects against high fat diet-induced hepatic steatosis without altering obesity or systemic lipid levels. Mechanistically, circulating FABP4 directly binds to hepatocytes, facilitating free fatty acid uptake. Furthermore, we developed a high-affinity humanized monoclonal antibody that selectively neutralizes circulating FABP4, blocks hepatocyte binding, suppresses fatty acid uptake, and markedly attenuates hepatic steatosis in multiple obese mouse models. These findings establish circulating FABP4 as a pathogenic lipid chaperone and a promising therapeutic target for obesity-associated hepatic steatosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/701451v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@5b91d5org.highwire.dtl.DTLVardef@1c34892org.highwire.dtl.DTLVardef@1d17ea9org.highwire.dtl.DTLVardef@d2b43c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHepatocytic accumulation of extrinsic FABP4 links adiposity to liver lipid deposition. C_LIO_LISpecific deletion of FABP4 in adipocytes prevents hepatic steatosis without affecting systemic lipid levels or obesity. C_LIO_LICirculating FABP4 derived from adipocytes directly binds hepatocytes to facilitate free fatty acid transfer. C_LIO_LIBlocking circulating FABP4 with a high-affinity anti-FABP4 monoclonal antibody inhibits hepatocyte lipid uptake and attenuates steatosis in multiple obese mouse models. C_LI

pathology↗

bioRxiv2024

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

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

immunology↗