The Switch: Mechanisms Governing Macrophage Phenotypic Variability in Liver Disease

Abstract

Macrophages are key effectors of innate immune response to pathogens and the initiation of inflammation, and they contribute to maintaining tissue homeostasis, tissue repair, and development (Wynn et al. 2013b). Macrophages also help shape the adaptive immune response through the presentation of foreign antigens and production of chemokines which facilitate the trafficking of adaptive immune cells to sights of inflammation and tissue damage (Newson et al. 2014). Macrophages are classified as either tissue resident (i.e., liver Kupffer cells, brain microglia, and alveolar macrophages in the lung) or recruited (monocyte−/bone marrow-derived macrophages). In mice, monocytes are subdivided based on their expression of Ly6C and CCR2. Ly6C^hi CCR2⁺ monocytes rapidly infiltrate tissue upon injury (Karlmark et al. 2009). During acute or chronic liver injury, Ly6C^hi monocyte-derived macrophages are the predominate macrophage subtype (Tacke and Randolph 2006; Karlmark et al. 2009). Ly6C^lowCCR2⁻ monocytes have been shown to exhibit a “patrolling” behavior and have been found crawling along the hepatic endothelium (Carlin et al. 2013). While monocyte-derived Ly6C^hi initially exert tissue-destructive properties, they can differentiate into Ly6C^low monocyte-derived macrophages which promote tissue repair and resolution of inflammation (Dal-Secco et al. 2015). The human monocyte counterparts are classified as classical (CD14^hiCD16⁻), intermediate (CD14⁺CD16⁺), and nonclassical (CD14^dimCD16⁺) (Ingersoll et al. 2010). Mouse and human monocytes share much similarity but differ in several aspects that must be taken into consideration when translating mouse and human studies. For instance, based on receptor expression CD16⁻ and Ly6C^hi, monocytes highly express CCR2, whereas CD16^hi and Ly6C^lo monocytes express high levels of CX₃CR1 (Geissmann et al. 2003; Tacke et al. 2007). However, in regard to FcγR1 expression, mRNA and protein expression is conserved between CD16⁻ and Ly6C^hi monocytes, whereas human CD16⁺ monocytes lose FcγR1 surface protein expression which is retained on Ly6C^low monocytes (Ingersoll et al. 2010). Furthermore, Ly6C^low monocytes are more instrumental in phagocytosis, whereas in humans, CD16⁻ monocytes are more phagocytic (Wildgruber et al. 2009; Tacke et al. 2006). Macrophages display a remarkable ability to alter their phenotype based on tissue microenvironmental cues such as hypoxia, cytokines, lipids, and exposure to dead cells. In acute and chronic liver diseases, various subsets of hepatic macrophages have been found to be involved in disease pathogenesis. In this review, we will summarize the development, heterogeneity, and plasticity of macrophages in response to microenvironmental stimuli in physiological and pathophysiological conditions of the liver.