Hepatic Macrophages and Macrophages with Different Functions in Hepatic Fibrosis

Macrophages are important cells with crucial roles in the homeostasis and regulation of immune response. They are heterogenous cells of mononuclear phagocytic system and display a wide range of patho-biological properties. Macrophages differ in ontogeny, morphology, immunophenotypes and functions. Three major types have been recognized: exudate macrophages, resident macrophages and dendritic cells. Exudate macrophages are in the monocytic lineage of monocytes, promonoblasts, monoblasts, and macrophagecolony forming unit (M-CFU) originating from hematopoietic stem cells in the bone marrow. Resident macrophages such as microglia, Kupffer cells, and alveolar macrophages also develop from hematopoietic stem cells; however, the precursors migrate from the bone marrow into connective tissues during ontogeny, and then differentiate into resident macrophages. Dendritic cells are composed of the interstitial dendritic cells, the interdigitating follicular cells of spleen and lymph nodes, and the Langerhans cells of the epidermis; the differentiation pathway is distinct from those of exudate or resident macrophages. Macrophages are scavengers or antigen presenting cells (APCs); they pick up, ingest and process foreign materials, and occasionally act as APCs by stimulating lymphocytes through the complicated immune system. Dendritic cells are more efficient in antigen presentation than other macrophages. Liver-specific macrophages during prenatal hepatogenesis until adulthood in rats, detectable by the immunohistochemistry with different antibodies, exhibit divergent properties including phagocytosis, proinflammatory cytokine productions, lipid metabolism and antigen presentation. Macrophages with phagocytic activity, which are predominant in prenatal period, maintain homeostasis by clearing apoptotic hematopoietic cells in the liver; additionally, hepatic macrophages play roles in homeostasis or host defense mechanisms through the production of proinflammatory cytokines, lipid metabolism and antigen No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. Hossain Md. Golbar and Jyoji Yamate 278 presentation in postnatal life. Hepatocyte injury, induced in perivenular areas by hepatotoxicants, is followed mainly by infiltration of exudate macrophages and activated resident macrophages, and APCs appear later. Chemically-induced cholangiocyte injury and subsequent biliary fibrosis in the Glisson’s sheath are accompanied by consistent appearance of APCs and infiltration of exudate macrophages and activated Kupffer cells is later for APCs. Among these diverse properties, functions relating to fibrosis have recently been focused on hepatic macrophages, because the setting is emerging as a worldwide public health problem; in this light, macrophages secrete soluble factors such as TGF-β1 capable of inducing myofibroblasts which can excessively produce extracellular matrices, leading to fibrogenesis. Based on macrophage properties which are different in early, mid and late stages of fibrosis, the concepts of the classically activated M1 (pro-inflammatory) macrophages and the alternatively activated M2 (reparative) macrophages have currently been proposed. Macrophages undergo functional changes from M1 to M2 (or vice versa) under microenvironmental conditions evoked by cell-cell interactions. In this chapter, the general notions of genesis, distribution and functions of macrophages, and the unique properties of hepatic macrophages, particularly in hepatic fibrosis, are addressed.