Macrophages are found in close proximity with collagen-producing myofibroblasts and indisputably play a key role in fibrosis. They produce profibrotic mediators that directly activate fibroblasts, including transforming growth factor-β1 and platelet-derived growth factor, and control extracellular matrix turnover by regulating the balance of various matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Macrophages also regulate fibrogenesis by secreting chemokines that recruit fibroblasts and other inflammatory cells. With their potential to act in both a pro- and antifibrotic capacity, as well as their ability to regulate the activation of resident and recruited myofibroblasts, macrophages and the factors they express are integrated into all stages of the fibrotic process. These various, and sometimes opposing, functions may be performed by distinct macrophage subpopulations, the identification of which is a growing focus of fibrosis research. Although collagen-secreting myofibroblasts once were thought of as the master “producers” of fibrosis, this review will illustrate how macrophages function as the master “regulators” of fibrosis.

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Macrophages: master regulators of inflammation and fibrosis.

A Meta-Analysis of Cytokines in Alzheimer's Disease

The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In mammals, despite the absence of endogenous chitin, a number of chitinases and chitinase-like proteins (C/CLPs) have been identified. However, their roles have only recently begun to be elucidated. Acidic mammalian chitinase (AMCase) inhibits chitin-induced innate inflammation; augments chitin-free, allergen-induced Th2 inflammation; and mediates effector functions of IL-13. The CLPs BRP-39/YKL-40 (also termed chitinase 3-like 1) inhibit oxidant-induced lung injury, augments adaptive Th2 immunity, regulates apoptosis, stimulates alternative macrophage activation, and contributes to fibrosis and wound healing. In accord with these findings, levels of YKL-40 in the lung and serum are increased in asthma and other inflammatory and remodeling disorders and often correlate with disease severity. Our understanding of the roles of C/CLPs in inflammation, tissue remodeling, and tissue injury in health and disease is reviewed below.

Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury.

Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma.

Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH) are becoming the leading cause of liver-related morbidity and mortality worldwide, and a primary indication for liver transplantation. The pathophysiology of NASH is multifactorial and not yet completely understood; however, innate immunity is a major contributing factor in which liver-resident macrophages (Kupffer cells) and recruited macrophages play a central part in disease progression. In this Review, we assess the evidence for macrophage involvement in the development of steatosis, inflammation and fibrosis in NASH. In this process, not only the polarization of liver macrophages towards a pro-inflammatory phenotype is important, but adipose tissue macrophages, especially in the visceral compartment, also contribute to disease severity and insulin resistance. Macrophage activation is mediated by factors such as endotoxins and translocated bacteria owing to increased intestinal permeability, factors released from damaged or lipoapoptotic hepatocytes, as well as alterations in gut microbiota and defined nutritional components, including certain free fatty acids, cholesterol and their metabolites. Reflecting the important role of macrophages in NASH, we also review studies investigating drugs that target macrophage recruitment to the liver, macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH.

The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Impact of gut microbiota on diabetes mellitus

Altered plasma cytokine levels in Alzheimer's disease: correlation with the disease progression.

Immuno-modulatory effects of vitamin D3 in human monocyte and macrophages.

Background and aims: Non-alcoholic steatohepatitis (NASH) is a clinicopathological condition characterised by a necroinflammatory disorder with fatty infiltration of the hepatocytes. The molecular mechanisms involved in the anomalous behaviour of liver cells have only partially been determined. Human chitotriosidase (Chit) is a chitinolytic enzyme mainly produced by activated macrophages. The aim of this study was to investigate the expression of the chitinase-like gene in Kupffer cells, to determine how chitotriosidase may be implicated in the progression from uncomplicated steatosis to steatohepatitis with progressive fibrosis. Methods: 75 subjects were studied: 40 with NASH, 20 with simple steatosis, and 15 normal controls. Kupffer cells obtained from liver biopsies were used to detect CHIT expression, superoxide anion (O 2 − ), lipid peroxidation, and tumour necrosis factor α (TNFα) and ferritin levels. Results: CHIT expression differed markedly in livers from normal controls and in those from patients with simple steatosis or non-alcoholic steatohepatitis. A significant correlation between mRNA CHIT and O 2 − , lipid peroxidation, TNFα, and ferritin levels was observed in both NASH and simple steatosis. Conclusions: Human Kupffer cells in NASH patients overproduce chitotriosidase. At the highest levels of production, this enzyme may play a role in increasing the risk for a poor outcome in steatohepatitis.

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Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease

Human chitotriosidase (Chit), a chitinolytic enzyme, is a member of the chitinase family. In human plasma, Chit activity has been proposed as a biochemical marker of macrophage activation in several lysosomal diseases. Recently we found that Chit activity is higher in patients affected by Plasmodium falciparum malaria infection, suggesting that Chit may reflect induction of an immunological response. To assess this hypothesis, we evaluated the CHIT1 mRNA levels in human monocytes/macrophages (HMMs) following treatment with interferon-gamma (IFNg), tumor necrosis factor-alpha (TNFa), and lipopolysaccharide (LPS). Stimulation of macrophages with INF-g, TNF-a, and LPS resulted in an increase in Chit activity as well as the levels of CHIT1 mRNA as measured by quantitative real-time PCR. The data presented in this article show that Chit plays a role in the response to the activation of INF-g-, TNF-a-, and LPS-driven macrophages, suggesting that the production of Chit by macrophages could have biological relevance in the immune-response. J. Clin. Lab. Anal. 19:128‐132, 2005. � c 2005

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M. Di Rosa

Papers

Impact of gut microbiota on diabetes mellitus

Altered plasma cytokine levels in Alzheimer's disease: correlation with the disease progression.

Immuno-modulatory effects of vitamin D3 in human monocyte and macrophages.

Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease

Interferon-gamma, tumor necrosis factor-alpha, and lipopolysaccharide promote chitotriosidase gene expression in human macrophages.