The Role of Tissue Macrophage-Mediated Inflammation on NAFLD Pathogenesis and Its Clinical Implications

Abstract

The obese phenotype is characterized by a state of chronic low-grade systemic inflammation that contributes to the development of comorbidities, including nonalcoholic fatty liver disease (NAFLD). In fact, NAFLD is often associated with adipocyte enlargement and consequent macrophage recruitment and inflammation. Macrophage polarization is often associated with the proinflammatory state in adipose tissue. In particular, an increase of M1 macrophages number or of M1/M2 ratio triggers the production and secretion of various proinflammatory signals (i.e., adipocytokines). Next, these inflammatory factors may reach the liver leading to local M1/M2 macrophage polarization and consequent onset of the histological damage characteristic of NAFLD. Thus, the role of macrophage polarization and inflammatory signals appears to be central for pathogenesis and progression of NAFLD, even if the heterogeneity of macrophages and molecular mechanisms that govern their phenotype switch remain incompletely understood. In this review, we discuss the role of adipose and liver tissue macrophage-mediated inflammation in experimental and human NAFLD. This focus is relevant because it may help researchers that approach clinical and experimental studies on this disease advancing the knowledge of mechanisms that could be targeted in order to revert NAFLD-related fibrosis.

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis

“…Macrophages perform a number of functions such as innate immunity, inflammation, host defense, and homeostatic functions such as regulation of metabolism, tissue repair, and remodeling . These functions are carried out by two well‐characterized distinct macrophage subsets, M1 and M2.…”

IFN-γ orchestrates tumor elimination, tumor dormancy, tumor escape, and progression

“…To this end, ultraviolet (UV)-induced cutaneous malignant melanoma can be abolished by systemic blockade of IFN- γ [43]. Non-alcoholic fatty liver disease (NAFLD) is also associated with the dominance of M1 macrophages which produce inflammatory cytokines, including IFN- γ [44, 45]. In fact, IFN- γ -induced protein 10 (IP-10) is elevated in patients with progressive NAFLD [46].…”

“…Dietary saturated fatty acids are major contributors to NAFLD through the activation of NF-kB, which is a key transcription factor for M1 macrophage activation [44, 47]. This, in turn, leads to inflammation-induced liver damage in nonalcoholic steatohepatitis (NASH) disease [45] and consequent progression to HCC [48, 49]. Even in the absence of NF-kB signaling, IFN- γ producing NKT cells actively participate in the pathogenesis of NASH disease [50].…”

Fat and hepatocellular carcinoma

“…As a consequence, macrophages are recruited in the site of inflammation and M1/M2 macrophage polarization is induced. The activation of macrophages stimulates the production of adipose tissue related adipocytokines, that, once released in the systemic circulation, reach different organs, including liver [25,26] . The inversion of M1/M2 ratio is due to the increase of M1 macrophages and reduction of M2 macrophages [26] .…”

“…The activation of macrophages stimulates the production of adipose tissue related adipocytokines, that, once released in the systemic circulation, reach different organs, including liver [25,26] . The inversion of M1/M2 ratio is due to the increase of M1 macrophages and reduction of M2 macrophages [26] . The higher number of M1 cells cause an over production of several pro-inflammatory cytokines, such as IL-1b, IL-6, IL-8, IL-12, and TNF-a.…”