Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner.
Immunodeficiency in chronic granulomatous disease (CGD) is well characterized. Less understood are exaggerated sterile inflammation and autoimmunity associated with CGD. Impaired recognition and clearance of apoptotic cells resulting in their disintegration may contribute to CGD inflammation. We hypothesized that priming of macrophages (Ms) with IFN-γ would enhance impaired engulfment of apoptotic cells in CGD. Diverse M populations from CGD (gp91(phox)(-/-)) and wild-type mice, as well as human Ms differentiated from monocytes and promyelocytic leukemia PLB-985 cells (with and without mutation of the gp91(phox)), demonstrated enhanced engulfment of apoptotic cells in response to IFN-γ priming. Priming with IFN-γ was also associated with increased uptake of Ig-opsonized targets, latex beads, and fluid phase markers, and it was accompanied by activation of the Rho GTPase Rac. Enhanced Rac activation and phagocytosis following IFN-γ priming were dependent on NO production via inducible NO synthase and activation of protein kinase G. Notably, endogenous production of TNF-α in response to IFN-γ priming was critically required for inducible NO synthase upregulation, NO production, Rac activation, and enhanced phagocytosis. Treatment of CGD mice with IFN-γ also enhanced uptake of apoptotic cells by M in vivo via the signaling pathway. Importantly, during acute sterile peritonitis, IFN-γ treatment reduced excess accumulation of apoptotic neutrophils and enhanced phagocytosis by CGD Ms. These data support the hypothesis that in addition to correcting immunodeficiency in CGD, IFN-γ priming of Ms restores clearance of apoptotic cells and may thereby contribute to resolution of exaggerated CGD inflammation.
Fernandez-Boyanapalli
Ruby
R
National Jewish Health, Denver, CO 80206, USA.
McPhillips
Kathleen A
KA
Frasch
S Courtney
SC
Janssen
William J
WJ
Dinauer
Mary C
MC
Riches
David W H
DW
Henson
Peter M
PM
Byrne
Aideen
A
Bratton
Donna L
DL
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D004789:Enzyme Activation / Q000276:immunology; D006105:Granulomatous Disease, Chronic / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D009569:Nitric Oxide; D007371:Interferon-gamma
J Clin Invest. 1993 Jun;91(6):2596-601
8390485
J Infect Dis. 2007 Sep 15;196(6):954-62
17703428
J Leukoc Biol. 2006 May;79(5):896-903
16641135
J Leukoc Biol. 2002 May;71(5):775-81
11994501
Science. 1993 Sep 10;261(5127):1445-8
7690156
Blood. 2001 Jul 15;98(2):436-41
11435314
J Immunol. 2007 Jun 15;178(12):8117-26
17548650
Am J Physiol Lung Cell Mol Physiol. 2006 Oct;291(4):L677-82
16766576
J Biol Chem. 2002 Dec 20;277(51):49965-75
12376550
Blood. 1997 Oct 15;90(8):3187-94
9376602
J Immunol. 2003 Sep 1;171(5):2610-5
12928413
Am J Physiol Cell Physiol. 2009 Sep;297(3):C621-31
19570889
Am J Respir Cell Mol Biol. 2010 Sep;43(3):342-8
19855087
J Immunol. 2008 Sep 1;181(5):3277-84
18713999
Cell Biol Int. 2007 Jun;31(6):565-9
17241792
Immunity. 2010 Jan 29;32(1):116-28
20079668
FASEB J. 2005 Jun;19(8):923-33
15923402
J Cell Biol. 2001 Nov 12;155(4):649-59
11706053
Medicine (Baltimore). 2000 May;79(3):170-200
10844936
Infect Immun. 2001 Oct;69(10):6391-400
11553583
J Interferon Cytokine Res. 2001 Aug;21(8):567-73
11559434
J Leukoc Biol. 2000 Oct;68(4):487-94
11037969
Medicine (Baltimore). 2000 May;79(3):155-69
10844935
Blood. 1995 Aug 1;86(3):1184-95
7542498
Glia. 2001 Jan;33(1):87-95
11169794
Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9832-6
8234321
Anal Biochem. 1982 Oct;126(1):131-8
7181105
J Immunol. 1995 Mar 1;154(5):2366-74
7532668
J Immunol. 1992 Dec 15;149(12):4029-35
1281199
J Leukoc Biol. 2003 May;73(5):591-9
12714573
J Immunol. 2001 Jun 1;166(11):6847-54
11359844
Cell Death Differ. 2006 Dec;13(12):2011-22
16628234
Infect Immun. 2005 Jun;73(6):3445-52
15908373
Infect Immun. 1995 Sep;63(9):3715-7
7642312
J Cell Sci. 2000 Sep;113 ( Pt 17):2955-61
10934035
Clin Rev Allergy Immunol. 2010 Feb;38(1):3-10
19504359
EMBO J. 1998 Nov 2;17(21):6219-29
9799231
Am J Pathol. 1985 Apr;119(1):101-10
2984939
Cell. 1992 Aug 7;70(3):401-10
1643658
Microbes Infect. 2008 Feb;10(2):175-84
18248765
J Biol Chem. 2006 Dec 15;281(50):38376-84
17056601
Inflammation. 1983 Sep;7(3):227-32
6681319
Nature. 2008 Jan 10;451(7175):211-5
18185592
Nat Rev Mol Cell Biol. 2008 Aug;9(8):639-49
18612320
Nat Genet. 1995 Feb;9(2):202-9
7719350
J Exp Med. 2003 Oct 6;198(7):987-97
14517275
J Exp Med. 1975 Nov 1;142(5):1150-64
53258
J Leukoc Biol. 2004 Feb;75(2):163-89
14525967
Essays Biochem. 2003;39:105-17
14585077
J Biol Chem. 2008 Nov 28;283(48):33736-49
18824544
Blood. 2009 Feb 26;113(9):2047-55
18952895
N Engl J Med. 1991 Feb 21;324(8):509-16
1846940
Nature. 2007 Nov 15;450(7168):430-4
17960134
Pediatrics. 2004 Aug;114(2):462-8
15286231
J Leukoc Biol. 2000 Jan;67(1):18-25
10647993
J Biol Chem. 1991 Dec 25;266(36):24785-92
1761573
Infect Immun. 1991 Jun;59(6):1893-8
1645327
Clin Diagn Lab Immunol. 1999 May;6(3):420-4
10225847
Clin Exp Immunol. 2002 Sep;129(3):479-84
12197889
J Immunol. 2009 Mar 1;182(5):3262-9
19234224
J Immunol. 1990 Dec 15;145(12):4290-7
2124240
J Biol Chem. 2009 Jun 19;284(25):17030-17038
19383607
J Immunol. 1999 Apr 15;162(8):4606-13
10202000
J Immunol. 2006 Sep 1;177(5):3218-24
16920961
J Leukoc Biol. 1992 Oct;52(4):369-76
1402387
Int Immunopharmacol. 2008 Dec 10;8(12):1633-8
18692597
J Immunol. 2001 Apr 15;166(8):4831-4
11290758