Depletion of Neutrophils Promotes the Resolution of Pulmonary Inflammation and Fibrosis in Mice Infected with Paracoccidioides brasiliensis.
Chronic stages of paracoccidioidomycosis (PCM) are characterized by granulomatous lesions which promote the development of pulmonary fibrosis leading to the loss of respiratory function in 50% of patients; in addition, it has been observed that neutrophils predominate during these chronic stages of P. brasiliensis infection. The goal of this study was to evaluate the role of the neutrophil during the chronic stages of experimental pulmonary PCM and during the fibrosis development and tissue repair using a monoclonal specific to this phagocytic cell. Male BALB/c mice were inoculated intranasally with 1.5x106 P. brasiliensis yeast cells. A monoclonal antibody specific to neutrophils was administered at 4 weeks post-inoculation followed by doses every 48h during two weeks. Mice were sacrificed at 8 and 12 weeks post-inoculation to assess cellularity, fungal load, cytokine/chemokine levels, histopathological analysis, collagen and expression of genes related to fibrosis development. Depletion of neutrophils was associated with a significant decrease in the number of eosinophils, dendritic cells, B cells, CD4-T cells, MDSCs and Treg cells, fungal load and levels of most of the pro-inflammatory cytokines/chemokines evaluated, including IL-17, TNF-α and TGF-β1. Recovery of lung architecture was also associated with reduced levels of collagen, high expression of TGF-β3, matrix metalloproteinase (MMP)-12 and -14, and decreased expression of tissue inhibitor metalloproteinase (TIMP)-2, and MMP-8. Depletion of neutrophils might attenuate lung fibrosis and inflammation through down-regulating TGF-β1, TNF-α, IL-17, MMP-8 and TIMP-2. These results suggest that neutrophil could be considered as a therapeutic target in pulmonary fibrosis induced by P. brasiliensis.
Medical and Experimental Mycology Unit, Corporación para Investigaciones Biológicas (CIB), Medellín, Colombia.
Juan David
JD
Puerta-Arias
Medical and Experimental Mycology Unit, Corporación para Investigaciones Biológicas (CIB), Medellín, Colombia.
Paula Andrea
PA
Pino-Tamayo
Medical and Experimental Mycology Unit, Corporación para Investigaciones Biológicas (CIB), Medellín, Colombia.|School of Microbiology, Universidad de Antioquia, Medellín, Colombia.
Julián Camilo
JC
Arango
School of Microbiology, Universidad de Antioquia, Medellín, Colombia.|Basic and Applied Microbiology Research Group (MICROBA), Universidad de Antioquia, Medellín, Colombia.
Ángel
http://orcid.org/0000-0002-7052-7938
Á
González
J Immunol. 2009 Jul 15;183(2):1279-90
19553529
J Pathol. 2003 Jul;200(4):448-64
12845612
J Exp Med. 2010 Aug 2;207(8):1609-16
20624887
Front Biosci. 2006 May 01;11:1569-76
16368537
Rev Inst Med Trop Sao Paulo. 2004 May-Jun;46(3):127-31
15286812
J Leukoc Biol. 2016 Mar;99(3):467-73
26428677
Immunity. 2003 Jan;18(1):109-20
12530980
Clin Microbiol Rev. 1993 Apr;6(2):89-117
8472249
Clin Exp Immunol. 1995 Jul;101(1):114-20
7621580
Infect Immun. 2012 May;80(5):1759-65
22392929
Mycopathologia. 2008 Apr-May;165(4-5):313-30
18777636
Rev Infect Dis. 1982 May-Jun;4(3):656-64
7123042
Rev Inst Med Trop Sao Paulo. 1988 Sep-Oct;30(5):336-50
3249901
Med Mycol. 2000 Apr;38(2):177-82
10817235
Chem Immunol Allergy. 2003;83:95-114
12947981
Nat Rev Immunol. 2006 Mar;6(3):173-82
16498448
Blood. 2005 Sep 1;106(5):1843-50
15886329
Microb Pathog. 2011 Dec;51(6):432-41
21896326
Eur J Immunol. 2003 Jun;33(6):1744-53
12778493
Ann N Y Acad Sci. 2014 Jun;1319:66-81
24850053
J Leukoc Biol. 2008 Jan;83(1):64-70
17884993
J Biol Chem. 1999 Jul 30;274(31):21491-4
10419448
Ann N Y Acad Sci. 1999 Jun 30;878:73-91
10415721
Dis Model Mech. 2011 Mar;4(2):165-78
21324931
J Exp Med. 2013 Jul 1;210(7):1283-99
23825232
Am J Trop Med Hyg. 1998 Apr;58(4):424-30
9574786
Infect Immun. 2010 Apr;78(4):1564-70
20145099
Int Arch Allergy Immunol. 2013;162(4):276-82
24136351
Int Immunopharmacol. 2013 Dec;17(4):1226-32
24144812
Rev Inst Med Trop Sao Paulo. 1992 Mar-Apr;34(2):85-90
1340036
J Leukoc Biol. 2006 Jun;79(6):1202-13
16603588
Infect Immun. 2010 Mar;78(3):1078-88
20008536
Mycoses. 1992 Nov-Dec;35(11-12):269-74
1302798
J Mol Biol. 2013 May 27;425(10):1815-25
23399546
Med Mycol. 2005 Aug;43(5):417-22
16178370
J Immunol. 2014 Feb 15;192(4):1745-52
24442441
Adv Immunol. 1999;73:369-509
10399011
Immunol Rev. 2000 Oct;177:195-203
11138776
Rev Inst Med Trop Sao Paulo. 2000 Mar-Apr;42(2):59-66
10810319
Cytokine. 2014 Sep;69(1):102-9
25022968
Scand J Immunol. 2009 Feb;69(2):73-9
19144080
Immunity. 2004 Aug;21(2):215-26
15308102
Blood. 1997 Aug 1;90(3):909-28
9242519
An Bras Dermatol. 2013 Sep-Oct;88(5):700-11
24173174
Am J Pathol. 2009 Jul;175(1):3-16
19497999
BMC Immunol. 2012 Dec 07;13:65
23216912
BMC Immunol. 2012 Dec 12;13:69
23234398
J Immunol. 2010 Nov 15;185(10):6190-7
20926800
Mycopathologia. 1986 Jun;94(3):133-44
3762654
Parasite Immunol. 2014 Jan;36(1):13-31
24102495
Pulm Pharmacol Ther. 2011 Feb;24(1):81-91
20851204
Curr Opin Cell Biol. 1998 Oct;10(5):602-8
9818170
Am J Pathol. 2000 May;156(5):1811-20
10793093
Med Mycol. 2011 Nov;49(8):785-98
21539506
Curr Protein Pept Sci. 2002 Aug;3(4):409-21
12370004
Proc Natl Acad Sci U S A. 1977 Mar;74(3):897-901
191839
J Infect Dis. 2009 Aug 15;200(4):647-56
19591573
Cytokine. 2014 May;67(1):36-43
24680480
Clin Exp Immunol. 2000 Apr;120(1):125-33
10759773
Infect Immun. 2013 May;81(5):1751-63
23478316
Infect Immun. 1998 Feb;66(2):800-6
9453644
Biochemistry (Mosc). 2008 Sep;73(9):970-84
18976213
Clin Infect Dis. 2003 Oct 1;37(7):898-904
13130400
J Infect. 2013 Nov;67(5):470-85
23872208
Med Mycol. 1999 Feb;37(1):19-24
10200930
Med Mycol. 1999 Aug;37(4):261-7
10421861
Rom J Morphol Embryol. 2010;51(2):215-28
20495735
Med Mycol. 2002 Apr;40(2):153-9
12058728
Immunity. 2000 Feb;12(2):121-7
10714678
BMC Infect Dis. 2006 Mar 17;6:55
16545113
Mediators Inflamm. 2016;2016:3183285
27642235
Am J Trop Med Hyg. 1998 Jul;59(1):66-72
9684630
Cell Host Microbe. 2015 Apr 8;17(4):507-14
25771792