Myeloid cell SphK2 deletion enhances antigen-presenting cell hepatic infiltration in a mouse model of metabolic dysfunction-associated steatohepatitis

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B692
Abstract ID: 4106

Presenting Author:
Kaitlyn Georgene Jackson , Graduate Research Assistant at Virginia Commonwealth Univ. Sch. of Med.

Abstract:

Metabolic dysfunction-associated steatohepatitis (MASH) is the fastest-rising etiology of liver cirrhosis-related hospitalizations worldwide; its prevalence is expected to increase with obesity. No FDA-approved treatments exist for MASH, and identifying novel therapeutic targets is imperative. The sphingosine kinase 2 (SphK2) enzyme is highly expressed in hepatocytes and macrophages. Recent studies have reported that SphK2-generated sphingosine-1-phosphate (S1P) suppresses macrophage proinflammatory signals. Moreover, SphK2 degradation enables macrophage reactive oxygen species (ROS) formation and cytokine production. Our previous studies show that hepatic SphK2 is downregulated in MASLD patients and mice fed a high-fat diet. However, the relationship between SphK2 and macrophage proinflammatory function in MASH is poorly defined. NanoString RNA multiplex revealed that global SphK2 knockout mice fed Western diet plus sugar water (WDSW) exhibit strong induction of innate response and antigen presentation-associated genes in hepatic tissue. Follow-up spectral flow cytometry utilizing WDSW-fed mice with myeloid cell-specific SphK2 deletion exhibited significantly increased monocyte-derived macrophages and classical dendritic cells (cDCs), with elevated MHCII expression, compared to WDSW-feeding alone. While further study is necessary, these data suggest SphK2 depletion may enhance antigen presentation in macrophages and, indirectly, cDCs during MASH pathological progression.