Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis

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.

Matrix Metalloproteinase-8 Augments Bacterial Clearance in a Juvenile sepsis Model

“…One study of adult human NETs identified MMP8 along the length of the NET; however, we were unable to consistently co-localize MMP8 along the juvenile murine NETs (26). This difference may be due to differences in antibody sensitivity or in murine and human NET composition and structure.…”

Impaired AMPK Activity Drives Age-Associated Acute Lung Injury after Hemorrhage

“…Metformin has been shown to suppress eosinophilic airway inflammation and reduce peribronchial fibrosis via AMPK activation in asthmatic mice (15). AMPK-induced MMP8 secretion in neutrophils has been implicated in causing lung destruction in human tuberculosis (16). AMPKa1 KO mice exposed to cigarette smoke have increased production of IL-8, leading to increased lung inflammation and emphysema (17).…”

Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery

“…Nevertheless, a recent in vitro study using cultured human neutrophils revealed that they secrete MMP8, which correlates with results found in vivo. MMP8 probably contributes to tissue damage resulting in cavitation and dissemination and is therefore a target for MMP inhibitors such as doxycycline [288]. .…”