title: Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization.
abstract: Recent evidence that excessive lipid accumulation can decrease cellular levels of autophagy and that autophagy regulates immune responsiveness suggested that impaired macrophage autophagy may promote the increased innate immune activation that underlies obesity. Primary bone marrow-derived macrophages (BMDM) and peritoneal macrophages from high-fat diet (HFD)-fed mice had decreased levels of autophagic flux indicating a generalized impairment of macrophage autophagy in obese mice. To assess the effects of decreased macrophage autophagy on inflammation, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages were fed a HFD and treated with low-dose lipopolysaccharide (LPS). Knockout mice developed systemic and hepatic inflammation with HFD feeding and LPS. This effect was liver specific as knockout mice did not have increased adipose tissue inflammation. The mechanism by which the loss of autophagy promoted inflammation was through the regulation of macrophage polarization. BMDM and Kupffer cells from knockout mice exhibited abnormalities in polarization with both increased proinflammatory M1 and decreased anti-inflammatory M2 polarization as determined by measures of genes and proteins. The heightened hepatic inflammatory response in HFD-fed, LPS-treated knockout mice led to liver injury without affecting steatosis. These findings demonstrate that autophagy has a critical regulatory function in macrophage polarization that downregulates inflammation. Defects in macrophage autophagy may underlie inflammatory disease states such as the decrease in macrophage autophagy with obesity that leads to hepatic inflammation and the progression to liver injury.
authors: a Department of Medicine and Marion Bessin Liver Research Center; Albert Einstein College of Medicine ; Bronx , NY USA.
authors: Kun
authors: K
authors: Liu
authors: Enpeng
authors: E
authors: Zhao
authors: Ghulam
authors: G
authors: Ilyas
authors: Gadi
authors: G
authors: Lalazar
authors: Yu
authors: Y
authors: Lin
authors: Muhammad
authors: M
authors: Haseeb
authors: Kathryn E
authors: KE
authors: Tanaka
authors: Mark J
authors: MJ
authors: Czaja
mesh_terms: D000273:Adipose Tissue / Q000276:immunology*; D000818:Animals; D001343:Autophagy / Q000276:immunology*; D016764:Cell Polarity; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
keywords: ARG1, arginase 1; BMDM, bone marrow-derived macrophages; CCL, chemokine (C-C motif) ligand; CD, chow diet; CHIL3/CHI3L3, chitinase-like 3; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; GPT, glutamic pyruvic transaminase, soluble; HFD, high-fat diet; IFNG, interferon gamma; IL, interleukin; Kupffer cells; LPS, lipopolysaccharide; MAP1LC3/LC3B, microtubule-associated protein 1 light chain 3 β; MAPK, mitogen-activated protein kinase; MGL2, macrophage galactose N-acetyl-galactosamine specific lectin 2; NOS2, nitric oxide synthase 2, inducible; PBS, phosphate-buffered saline; PTGS2, prostaglandin-endoperoxide synthase 2; RETNLA, resistin like α;; STAT, signal transducer and activator of transcription; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling; WAT, white adipose tissue; autophagy; innate immunity; lipopolysaccharide; macrophage; obesity; polarization; qRT-PCR, quantitative real-time PCR; steatohepatitis
references: Hepatology. 2013 Mar;57(3):995-1004
references: 23081825
references: Am J Physiol. 1998 Oct;275(4 Pt 1):C1058-66
references: 9755059
references: J Biol Chem. 2006 Jun 2;281(22):15258-67
references: 16571730
references: Nature. 2006 Jun 15;441(7095):885-9
references: 16625204
references: J Clin Invest. 2007 Jan;117(1):175-84
references: 17200717
references: Nat Genet. 2007 Feb;39(2):207-11
references: 17200669
references: FASEB J. 2010 Aug;24(8):3052-65
references: 20375270
references: Cell Metab. 2010 Jun 9;11(6):467-78
references: 20519119
references: Mol Cancer. 2014;13:43
references: 24580730
references: Gastroenterology. 2010 Nov;139(5):1740-52
references: 20659474
references: Annu Rev Pharmacol Toxicol. 2011;51:267-88
references: 20887196
references: Nature. 2011 Jan 13;469(7329):221-5
references: 21124315
references: Nature. 2011 Jan 20;469(7330):323-35
references: 21248839
references: Annu Rev Pathol. 2011;6:275-97
references: 21034223
references: J Clin Endocrinol Metab. 2011 Feb;96(2):E268-77
references: 21047928
references: Nat Immunol. 2011 Mar;12(3):222-30
references: 21151103
references: J Clin Invest. 2011 Mar;121(3):985-97
references: 21317534
references: Annu Rev Immunol. 2011;29:415-45
references: 21219177
references: Trends Endocrinol Metab. 2011 Jun;22(6):234-40
references: 21419642
references: J Clin Invest. 2011 Jul;121(7):2736-49
references: 21670502
references: Cell. 2011 Sep 2;146(5):682-95
references: 21884931
references: Biochem Biophys Res Commun. 2011 Sep 9;412(4):618-25
references: 21856284
references: EMBO J. 2011 Nov 30;30(23):4701-11
references: 22068051
references: Curr Opin Immunol. 2012 Feb;24(1):21-31
references: 22118953
references: J Clin Invest. 2012 Mar;122(3):787-95
references: 22378047
references: Blood. 2012 Mar 22;119(12):2895-905
references: 22223827
references: Cell Metab. 2012 Jul 3;16(1):44-54
references: 22768838
references: Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):E3168-76
references: 23093667
references: Endocrinology. 2012 Dec;153(12):5866-74
references: 23117929
references: Cell Death Differ. 2013 Jan;20(1):3-11
references: 22595754
references: Science. 2013 Jan 11;339(6116):218-22
references: 23223452
references: Cell Death Differ. 2013 Mar;20(3):515-23
references: 23175187
references: Nat Rev Immunol. 2013 Oct;13(10):722-37
references: 24064518
references: Hepatology. 2013 Nov;58(5):1644-54
references: 23686698
references: Autophagy. 2014 Feb;10(2):192-200
references: 24300480
references: Diabetes. 2007 Jul;56(7):1761-72
references: 17456850
references: EMBO J. 2008 Apr 9;27(7):1110-21
references: 18337753
references: Cell Metab. 2008 Jun;7(6):496-507
references: 18522831
references: Cell Metab. 2008 Oct;8(4):325-32
references: 18840363
references: Cell Host Microbe. 2008 Nov 13;4(5):458-69
references: 18996346
references: Nature. 2008 Nov 13;456(7219):264-8
references: 18849965
references: Nat Rev Immunol. 2008 Dec;8(12):958-69
references: 19029990
references: Nature. 2009 Apr 30;458(7242):1131-5
references: 19339967
references: Diabetes. 2010 Feb;59(2):347-57
references: 19934001
references: Cell. 2010 Feb 5;140(3):313-26
references: 20144757
references: Annu Rev Physiol. 2010;72:219-46
references: 20148674
references: Immunity. 2010 May 28;32(5):593-604
references: 20510870
references: Transgenic Res. 1999 Aug;8(4):265-77
references: 10621974
references: J Biol Chem. 2000 Dec 22;275(51):40155-62
references: 11016920
references: JAMA. 2002 Jan 16;287(3):356-9
references: 11790215
references: Immunity. 2003 Dec;19(6):793-802
references: 14670297
references: J Clin Invest. 2003 Dec;112(12):1821-30
references: 14679177
references: J Biol Chem. 2004 Jul 23;279(30):31089-97
references: 15145937
references: J Leukoc Biol. 1994 Jun;55(6):723-8
references: 8195698
references: Diabetes. 2005 Aug;54(8):2277-86
references: 16046292