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Understanding Macrophage Complexity in Metabolic Dysfunction-Associated Steatotic Liver Disease: Transitioning from
Forkan Ahamed1, Natalie Eppler1, Elizabeth Jones1
1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Abstract:
Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), with MASH posing a risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The global prevalence of MASLD is estimated at approximately a quarter of the population, with significant healthcare costs and implications for liver transplantation. The pathogenesis of MASLD involves intrahepatic liver cells, extrahepatic components, and immunological aspects, particularly the involvement of macrophages. Hepatic macrophages are a crucial cellular component of the liver and play important roles in liver function, contributing significantly to tissue homeostasis and swift responses during pathophysiological conditions. Recent advancements in technology have revealed the remarkable heterogeneity and plasticity of hepatic macrophage populations and their activation states in MASLD, challenging traditional classification methods like the M1/M2 paradigm and highlighting the coexistence of harmful and beneficial macrophage phenotypes that are dynamically regulated during MASLD progression. This complexity underscores the importance of considering macrophage heterogeneity in therapeutic targeting strategies, including their distinct ontogeny and functional phenotypes. This review provides an overview of macrophage involvement in MASLD progression, combining traditional paradigms with recent insights from single-cell analysis and spatial dynamics. It also addresses unresolved questions and challenges in this area.
Insights
Metabolic dysfunction-associated steatotic liver disease (MASLD) involves complex macrophage roles. Understanding macrophage heterogeneity is key for developing new therapies for this widespread liver condition.
Area of Science:
- Hepatology
- Immunology
- Cell Biology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) affects roughly 25% of the global population, encompassing metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH).
- MASH is a significant risk factor for severe liver conditions like cirrhosis and hepatocellular carcinoma (HCC), imposing substantial healthcare burdens.
- The liver's immune microenvironment, particularly hepatic macrophages, plays a critical role in MASLD pathogenesis, influencing disease progression and outcomes.
Purpose of the Study:
- To review the multifaceted involvement of hepatic macrophages in the progression of MASLD.
- To integrate traditional understandings of macrophage function with recent single-cell and spatial analyses in MASLD.
- To highlight the heterogeneity and plasticity of macrophage populations in MASLD and their therapeutic implications.
Main Methods:
- Review of existing literature on hepatic macrophages and MASLD.
- Analysis of recent technological advancements, including single-cell sequencing and spatial transcriptomics.
- Synthesis of data from traditional M1/M2 macrophage paradigms and novel findings.
Main Results:
- Hepatic macrophages exhibit significant heterogeneity and plasticity in MASLD, challenging the simplistic M1/M2 classification.
- Both detrimental and beneficial macrophage phenotypes coexist and are dynamically regulated during MASLD progression.
- Macrophage ontogeny and diverse functional states are critical considerations for therapeutic strategies.
Conclusions:
- Hepatic macrophages are central players in MASLD, with complex and dynamic roles.
- Targeting specific macrophage phenotypes and understanding their heterogeneity offers promising therapeutic avenues for MASLD.
- Further research is needed to address unresolved questions regarding macrophage involvement in MASLD progression.
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