Abstract
Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease.
Highlights
The lung cavity is a hallmark of pulmonary tuberculosis, a globally important disease of man
We show that neutrophils secrete the collagenase matrix metalloproteinase-8 (MMP-8) in response to direct infection with Mycobacterium tuberculosis and via cellular networks
matrix metalloproteinases (MMPs)-8 is up-regulated in respiratory samples from TB patients, driving matrix destruction associated with neutrophil activation and reflects disease severity
Summary
The lung cavity is a hallmark of pulmonary tuberculosis, a globally important disease of man. Excessive neutrophil recruitment associates with pathology in animal models [2, 3] and in man [4] but the mechanism of how neutrophils drive pathology in human TB is not defined. Zinc-containing matrix metalloproteinases (MMPs) have key roles in the inflammatory immunopathology in a wide range of diseases including cancer and arthritis [5, 6]. Collagenases, a subgroup of the MMPs, are key in TB pathology since collagen is the main structural protein of the lung, the primary site of infection. Neutrophils secrete MMP-8, a potent collagenase, and increased neutrophil-derived MMPs associate with disease severity in CNS-TB [11, 12], implicating neutrophils in the immunopathology of human TB
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