Focus
Authors: Scott L. Friedman
Journal: Journal of Hepatology (2012)

Ilya Metchnikoff is widely hailed as the father of modern immunology based on his prescient characterization in the late 19th Century of the macrophage’s roles in phagocytic clearance of infections, tissue development and wound repair [[1]Stefater 3rd, J.A. Ren S. Lang R.A. Duffield J.S. Metchnikoff’s policemen: macrophages in development, homeostasis and regeneration.Trends Mol Med. 2011; 17: 743-752Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar]. In the ensuing ∼120 years, his paradigm of macrophage function has remained largely intact, albeit with a greater appreciation for their functional complexity. In addition to those classical functions identified by Metchnikoff, macrophages can also regulate hematopoiesis, reproduction, vasoregulation, apoptosis, cancer metastasis and lipid metabolism [1Stefater 3rd, J.A. Ren S. Lang R.A. Duffield J.S. Metchnikoff’s policemen: macrophages in development, homeostasis and regeneration.Trends Mol Med. 2011; 17: 743-752Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 2Qian B.Z. Pollard J.W. Macrophage diversity enhances tumor progression and metastasis.Cell. 2010; 141: 39-51Abstract Full Text Full Text PDF PubMed Scopus (2995) Google Scholar]. Moreover, there is a growing understanding of macrophage specialization, with their classification into two major subtypes, M1 and M2, which are distinguished primarily by the type of inflammation they elicit. M1 macrophages drive Th1 lymphocyte responses characterized by secretion of interleukin-1, interleukin-6 and tumor necrosis factor alpha, whereas M2 macrophages primarily drive allergic responses with killing and encapsulation of parasites typical of Th2 responses, with secretion of interleukin-4 and interleukin-13 [[3]Mantovani A. Sica A. Sozzani S. Allavena P. Vecchi A. Locati M. The chemokine system in diverse forms of macrophage activation and polarization.Trends Immunol. 2004; 25: 677-686Abstract Full Text Full Text PDF PubMed Scopus (4119) Google Scholar]. In reality, there is a continuum of macrophage phenotypes between these two ends of the spectrum, featuring evolving patterns of secretion of interleukins, chemokines, reactive oxygen species, and expression of membrane receptors [[3]Mantovani A. Sica A. Sozzani S. Allavena P. Vecchi A. Locati M. The chemokine system in diverse forms of macrophage activation and polarization.Trends Immunol. 2004; 25: 677-686Abstract Full Text Full Text PDF PubMed Scopus (4119) Google Scholar]. Indeed, flow cytometry can be used to characterize and isolate macrophage subtypes based on their cell surface receptor expression [[4]Heymann F. Hammerich L. Storch D. Bartneck M. Huss S. Russeler V. et al.Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice.Hepatology. 2012; 55: 898-909Crossref PubMed Scopus (113) Google Scholar]. Macrophage heterogeneity can also be tracked by their patterns of transcriptional regulation, with sequence-specific transcription factors and epigenetic changes driving macrophage identity and polarization [[5]Lawrence T. Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity.Nat Rev Immunol. 2011; 11: 750-761Crossref PubMed Scopus (1294) Google Scholar]. Two liver diseases where macrophage polarization is especially pertinent are hepatic fibrosis and fatty liver disease. A seminal study in 2005 demonstrated divergent roles of macrophages in experimental liver fibrosis, in which their depletion during fibrosis progression attenuated fibrosis, whereas their depletion during fibrosis regression made fibrosis worse [[6]Duffield J.S. Forbes S.J. Constandinou C.M. Clay S. Partolina M. Vuthoori S. et al.Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.J Clin Invest. 2005; 115: 56-65Crossref PubMed Scopus (1210) Google Scholar]. With a clearer appreciation for the polarity of macrophages, it is increasingly likely that these opposing roles of macrophages are accounted for by different subpopulations within the liver [[4]Heymann F. Hammerich L. Storch D. Bartneck M. Huss S. Russeler V. et al.Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice.Hepatology. 2012; 55: 898-909Crossref PubMed Scopus (113) Google Scholar], as well as by the contribution of related innate immune cells, especially dendritic cells [[7]Jiao J. Sastre D. Fiel M.I. Lee U.E. Ghiassi-Nejad Z. Ginhoux F. et al.Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression.Hepatology. 2012; 55: 244-255Crossref PubMed Scopus (101) Google Scholar]. Similarly, in non-alcoholic fatty liver disease (NAFLD), there is altered composition of macrophages, with an increase in M1 cytokines and Th1 lymphocytes in both liver [[8]Baffy G. Kupffer cells in non-alcoholic fatty liver disease: the emerging view.J Hepatol. 2009; 51: 212-223Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar] and adipose [[9]Lumeng C.N. Bodzin J.L. Saltiel A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization.J Clin Invest. 2007; 117: 175-184Crossref PubMed Scopus (3108) Google Scholar]. Moreover, many signaling pathways regulating inflammatory signaling converge with those controlling lipid metabolism to explain how fat alterations may modulate inflammation [10Gregor M.F. Hotamisligil G.S. Inflammatory mechanisms in obesity.Annu Rev Immunol. 2011; 29: 415-445Crossref PubMed Scopus (2295) Google Scholar, 11Lumeng C.N. Saltiel A.R. Inflammatory links between obesity and metabolic disease.J Clin Invest. 2011; 121: 2111-2117Crossref PubMed Scopus (1504) Google Scholar]. The paper by Leroux et al. in this issue of the Journal, adds to the mounting evidence that hepatic fat accumulation alters macrophage biology, which contributes to NAFLD pathogenesis associated with the metabolic syndrome. In this study, hepatic macrophages (Kupffer cells) were characterized in normal mice fed a high-fat diet for 16 weeks, and in congenitally obese ob/ob mice, which lack leptin. Cells were analyzed by flow cytometry, lipid content, gene expression and their ability to recruit lymphocytes. Interestingly, total Kupffer cell numbers were not affected, yet functional changes in the cells from fatty livers were significant. Specifically, there were enlarged lipid droplets with increased levels of diacylglycerols and ceramides, the latter of which are associated with increased apoptosis and stimulation of macrophage activation in the metabolic syndrome [[12]Bhargava P. Lee C.H. Role and function of macrophages in the metabolic syndrome.Biochem J. 2012; 442: 253-262Crossref PubMed Scopus (90) Google Scholar]. There was also induction of lipogenic and inflammatory gene expression (IL-6, IL1β and CXCL10) in Kupffer cells from fatty livers, which could be attenuated by inhibiting acetyl-CoA carboxylase, the first step in lipogenesis. Moreover, Kupffer cells from fatty livers were more sensitive to LPS stimulation, with enhanced recruitment of CD45+, CD4+ and CD8+ lymphocytes into the liver. Together, these data further implicate macrophages in the inflammation associated with hepatic fat accumulation. They also highlight the interesting question of how intracellular lipid alterations contribute to hepatic macrophage polarization, an issue not fully explored in prior studies. Above all, the findings clearly demonstrate that it is a phenotypic polarization of macrophages rather than a change in cell number that accounts for their contribution to inflammation in fatty liver. What are the translational implications of these findings? One day it may be possible to therapeutically enhance macrophage plasticity through several approaches. First, the knowledge of epigenetic regulation of macrophage phenotype has led to selective interference of inflammation by altering chromatin-dependent gene regulation [[13]Nicodeme E. Jeffrey K.L. Schaefer U. Beinke S. Dewell S. Chung C.W. et al.Suppression of inflammation by a synthetic histone mimic.Nature. 2010; 468: 1119-1123Crossref PubMed Scopus (1115) Google Scholar]. Second, a recent study has demonstrated that soluble amyloid P protein, a circulating pattern recognition molecule, alters macrophage phenotype to facilitate clearance of debris and suppress pro-inflammatory gene expression thereby reducing experimental fibrosis [[14]Castano A.P. Lin S.L. Surowy T. Nowlin B.T. Turlapati S.A. Patel T. et al.Serum amyloid P inhibits fibrosis through Fc gamma R-dependent monocyte-macrophage regulation in vivo.Sci Transl Med. 2009; 1: 5-13Crossref Scopus (162) Google Scholar]. Finally, there is the prospect of ex vivo manipulation and expansion following isolation of endogenous macrophage populations in order to deliver therapeutic cell populations that reduce inflammation and alter disease. While these approaches are not likely to alter the outcome of the chronic systemic disease of metabolic syndrome with NAFLD in the in the near term, the clarification of how macrophages contribute to its pathogenesis allows us to define diagnostic and therapeutic targets for the future, a prospect that owes its origins to the work of a 19th Century immunologist. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.