Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis.
Pulmonary tuberculosis (TB) is characterized by oxidative stress and lung tissue destruction by matrix metalloproteinases (MMPs). The interplay between these distinct pathological processes and the implications for TB diagnosis and disease staging are poorly understood. Heme oxygenase-1 (HO-1) levels were previously shown to distinguish active from latent TB, as well as successfully treated Mycobacterium tuberculosis infection. MMP-1 expression is also associated with active TB. In this study, we measured plasma levels of these two important biomarkers in distinct TB cohorts from India and Brazil. Patients with active TB expressed either very high levels of HO-1 and low levels of MMP-1 or the converse. Moreover, TB patients with either high HO-1 or MMP-1 levels displayed distinct clinical presentations, as well as plasma inflammatory marker profiles. In contrast, in an exploratory North American study, inversely correlated expression of HO-1 and MMP-1 was not observed in patients with other nontuberculous lung diseases. To assess possible regulatory interactions in the biosynthesis of these two enzymes at the cellular level, we studied the expression of HO-1 and MMP-1 in M. tuberculosis-infected human and murine macrophages. We found that infection of macrophages with live virulent M. tuberculosis is required for robust induction of high levels of HO-1 but not MMP-1. In addition, we observed that CO, a product of M. tuberculosis-induced HO-1 activity, inhibits MMP-1 expression by suppressing c-Jun/AP-1 activation. These findings reveal a mechanistic link between oxidative stress and tissue remodeling that may find applicability in the clinical staging of TB patients.
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Unidade de Medicina Investigativa, Laboratório Integrado de Microbiologia e Imunorregulação, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; bruno.andrade@bahia.fiocruz.br.
Bruno B
http://orcid.org/0000-0001-6833-3811
BB
Andrade
National Institutes of Health, International Center for Excellence in Research, Chennai 600031, India; National Institute for Research in Tuberculosis, Chennai 600031, India;
Nathella
N
Pavan Kumar
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Eduardo P
EP
Amaral
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Nicolas
http://orcid.org/0000-0003-1306-6466
N
Riteau
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Katrin D
KD
Mayer-Barber
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Kevin W
KW
Tosh
Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Nolan
N
Maier
Unidade de Medicina Investigativa, Laboratório Integrado de Microbiologia e Imunorregulação, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil;
Elisabete L
EL
Conceição
Department of Medicine, Imperial College London, London SW7 2AZ, United Kingdom;
Andre
A
Kubler
Government Stanley Medical Hospital, Chennai 600001, India;
Rathinam
R
Sridhar
National Institute for Research in Tuberculosis, Chennai 600031, India;
Vaithilingam V
VV
Banurekha
National Institute for Research in Tuberculosis, Chennai 600031, India;
Mohideen S
MS
Jawahar
Unidade de Medicina Investigativa, Laboratório Integrado de Microbiologia e Imunorregulação, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil;
Theolis
T
Barbosa
Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
Vincent C
VC
Manganiello
Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
Joel
J
Moss
Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
Joseph R
JR
Fontana
Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Beatriz E
BE
Marciano
Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Elizabeth P
EP
Sampaio
Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Kenneth N
KN
Olivier
Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Steven M
SM
Holland
Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD 20892;
Sharon H
SH
Jackson
Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Mahtab
M
Moayeri
Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Stephen
S
Leppla
Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Irini
I
Sereti
T-Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Daniel L
DL
Barber
Helminth Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Thomas B
TB
Nutman
National Institutes of Health, International Center for Excellence in Research, Chennai 600031, India; Helminth Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Subash
S
Babu
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Alan
A
Sher
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001938:Brazil; D005260:Female; D051547:Heme Oxygenase-1 / Q000097:blood* / Q000378:metabolism; D006801:Humans; D007194:India; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053779:Latent TGF-beta Binding Proteins / Q000097:blood; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000382:microbiology / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000097:blood*; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D018384:Oxidative Stress / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D014481:United States; D055815:Young Adult
D015415:Biomarkers; C509032:LTBP1 protein, human; D053779:Latent TGF-beta Binding Proteins; D018808:Transcription Factor AP-1; D051547:Heme Oxygenase-1; D048031:JNK Mitogen-Activated Protein Kinases; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1