Macrophage RAGE activation is proinflammatory in NASH

Gopanandan Parthasarathy; Amy S. Mauer; Naresh Golla; P. Vineeth Daniel; Lily H. Kim; Guneet S. Sidhu; George W. Marek 3rd; Emilien Loeuillard; Anuradha Krishnan; Hyun Se Kim Lee; Kevin D. Pavelko; Michael Charlton; Petra Hirsova; Sumera I. Ilyas; Harmeet Malhi

doi:10.1172/jci.insight.169138

Macrophage RAGE activation is proinflammatory in NASH

Gopanandan Parthasarathy,¹ Amy S. Mauer,¹ Naresh Golla,¹ P. Vineeth Daniel,¹ Lily H. Kim,² Guneet S. Sidhu,³ George W. Marek 3rd,¹ Emilien Loeuillard,¹ Anuradha Krishnan,¹ Hyun Se Kim Lee,¹ Kevin D. Pavelko,⁴ Michael Charlton,⁵ Petra Hirsova,¹ Sumera I. Ilyas,¹ and Harmeet Malhi¹

Published January 4, 2024 - More info

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Abstract

Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte derived macrophages. The receptor for advanced glycation end products (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE expressing macrophages are proinflammatory and mediate liver inflammation in NASH. Compared to healthy controls, RAGE expression was increased in liver biopsies from human NASH patients. In a high -fat, -fructose, and -cholesterol (FFC)-induced murine model of NASH, RAGE expression was increased, specifically on recruited macrophages. FFC mice that received a pharmacological inhibitor of RAGE (TTP488), and myeloid-specific RAGE knockout mice (RAGE-MKO) had attenuated liver injury associated with a reduced accumulation of RAGE⁺ recruited macrophages. Transcriptomic analysis suggested that pathways of macrophage and T-cell activation were upregulated by FFC diet, inhibited by TTP488 treatment, and reduced in RAGE-MKO mice. Correspondingly, the secretome of ligand-stimulated bone marrow derived macrophages from RAGE-MKO mice had an attenuated capacity to activate CD8⁺ T cells. Our data implicate RAGE as what we propose to be a novel and potentially targetable mediator of the proinflammatory signaling of recruited macrophages in NASH.

Macrophage RAGE activation is proinflammatory in NASH

Gopanandan Parthasarathy,¹ Amy S. Mauer,¹ Naresh Golla,¹ P. Vineeth Daniel,¹ Lily H. Kim,² Guneet S. Sidhu,³ George W. Marek 3rd,¹ Emilien Loeuillard,¹ Anuradha Krishnan,¹ Hyun Se Kim Lee,¹ Kevin D. Pavelko,⁴ Michael Charlton,⁵ Petra Hirsova,¹ Sumera I. Ilyas,¹ and Harmeet Malhi¹

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Macrophage RAGE activation is proinflammatory in NASH

Gopanandan Parthasarathy,1 Amy S. Mauer,1 Naresh Golla,1 P. Vineeth Daniel,1 Lily H. Kim,2 Guneet S. Sidhu,3 George W. Marek 3rd,1 Emilien Loeuillard,1 Anuradha Krishnan,1 Hyun Se Kim Lee,1 Kevin D. Pavelko,4 Michael Charlton,5 Petra Hirsova,1 Sumera I. Ilyas,1 and Harmeet Malhi1

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Gopanandan Parthasarathy,¹ Amy S. Mauer,¹ Naresh Golla,¹ P. Vineeth Daniel,¹ Lily H. Kim,² Guneet S. Sidhu,³ George W. Marek 3rd,¹ Emilien Loeuillard,¹ Anuradha Krishnan,¹ Hyun Se Kim Lee,¹ Kevin D. Pavelko,⁴ Michael Charlton,⁵ Petra Hirsova,¹ Sumera I. Ilyas,¹ and Harmeet Malhi¹