Macrophage RAGE activation is proinflammatory in NASH

Area of Science:

• Immunology
• Hepatology
• Molecular Biology

Background:

• Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are diverse, including proinflammatory monocyte-derived macrophages.
• The receptor for advanced glycation endproducts (RAGE) is present on macrophages and activated by damage-associated molecular patterns (DAMPs) in NASH.
• The specific role of macrophage RAGE signaling in NASH pathogenesis remains unclear.

Purpose of the Study:

• To investigate the hypothesis that RAGE-expressing macrophages are proinflammatory and contribute to liver inflammation in NASH.
• To explore RAGE as a potential therapeutic target in NASH.

Main Methods:

• Analysis of RAGE expression in human NASH liver biopsies and a murine model of NASH induced by a high-fat, -fructose, and -cholesterol (FFC) diet.
• Pharmacological inhibition of RAGE using TTP488 and genetic ablation of RAGE in myeloid cells (RAGE-MKO mice).
• Assessment of liver injury, macrophage infiltration, transcriptomics, and T cell activation.

Main Results:

• RAGE expression was elevated in NASH patients and specifically on recruited macrophages in the FFC-induced NASH model.
• RAGE inhibition (TTP488) and myeloid-specific RAGE knockout (RAGE-MKO) attenuated liver injury and reduced RAGE+ macrophage accumulation.
• FFC diet upregulated macrophage and T cell activation pathways, which were inhibited by TTP488 and reduced in RAGE-MKO mice.
• Macrophage secretomes from RAGE-MKO mice showed reduced capacity to activate CD8+ T cells.

Conclusions:

• RAGE signaling in recruited macrophages is implicated in promoting liver inflammation in NASH.
• RAGE represents a novel and potentially targetable mediator of proinflammatory macrophage activity in NASH.