Pathophysiological mechanisms and therapeutic potentials of macrophages in non-alcoholic steatohepatitis

ABSTRACT

Introduction: Non-alcoholic steatohepatitis (NASH), a hepatic manifestation of metabolic syndrome, is a major cause of morbidity and healthcare burden worldwide. While the molecular pathogenesis of NASH remains unclear and therapeutic options are limited, inflammation is recognized as an essential factor for NASH development. Factors that link NASH to inflammation are macrophages and their secreted cytokines.

Areas covered: This review summarizes the current knowledge of macrophage-mediated molecular pathways in NASH to shed insights on potential pharmacotherapeutic applications.

Expert opinion: Macrophages are not only known for their role of phagocytosis in innate immunity, but also for both extrinsic and intrinsic regulation of inflammatory functions of many cytokines. Recent advances have revealed the effects of macrophage recruitment and polarization on the development of NASH. We and others have shown that the proliferation of hepatic macrophages and the subsequent production of pro-inflammatory cytokines initiates inflammatory cascades, orchestrates activities of transcription factors involved in lipid metabolism/translocation, and modulates programmed cell death. Together, these findings support the pathophysiological role of macrophages in the pathogenesis of NASH. Thus, evaluating potential therapeutic targets against the infiltration and/or polarization of specific macrophage subtypes is of clinical interest for alleviation of early-stage NASH, with the goal of halting disease progression.

KEYWORDS:

• Macrophage
• inflammation
• lipid metabolism
• oxidative stress
• autophagy

Article highlights.

• Alteration of macrophage phenotypes and secretion of cytokines/chemokines are key indicators of nonalcoholic steatohepatitis (NASH) development.

• Macrophages promote the development of NASH by initiating inflammatory cascades, orchestrating activities of transcription factors involved in lipid metabolism/translocation, enhancing expression of redox enzymes in oxidative stress response, and modulating programmed cell death.

• Targeting macrophage and its secreted cytokines is a promising therapeutic option for NASH.

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Financial & competing interests disclosure

The authors were supported by the Collaborative Research Fund of the Research Grant Council Hong Kong under grant numbers CUHK3/CRF/12R and HKU3/CRF11R; the National Basic Research Program of China under (973 program) under grant number 2013CB531401; the Theme-based Research Scheme of the Hong Kong Research Grants Council under grant number T12-403-11 and the Shenzhen Virtual University Park Support Scheme awarded to the CUHK Shenzhen Research Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.