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

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.肺空洞是结核病（tuberculosis, TB）的标志性病理特征，其以极高的分枝杆菌载量为特点，并会持续维持结核分枝杆菌（M. tuberculosis）的传播循环。目前，介导空洞形成的基质破坏机制尚未完全阐明。中性粒细胞正逐渐被认为是结核病免疫病理损伤的关键介导因子，其浸润与不良预后密切相关。本研究通过细胞模型、108例患者队列以及独立的患者肺活检样本，探究了结核病相关基质破坏所依赖的中性粒细胞介导机制。研究发现，结核病患者体内中性粒细胞来源的、依赖核因子κB（NF-κB）的基质金属蛋白酶8（matrix metalloproteinase-8, MMP-8）分泌显著上调，且该因子可在体外实验及结核病患者的呼吸道样本中诱导基质破坏。结核分枝杆菌感染诱导的胶原破坏可被多西环素——一种已获批上市的基质金属蛋白酶抑制剂——阻断。中性粒细胞胞外陷阱（neutrophil extracellular traps, NETs）中含有MMP-8，且在结核病患者的样本中数量显著升高。中性粒细胞附着于人肺结核空洞的周边区域，且痰液中的MMP-8浓度可反映结核病的影像学及临床疾病严重程度。腺苷酸活化蛋白激酶（AMPK）作为分解代谢的核心调控因子，可促进中性粒细胞分泌MMP-8；而腺苷酸活化蛋白激酶缺陷患者的中性粒细胞分泌的MMP-8浓度更低。在人类结核病肺活检样本中可检测到表达AMPK的中性粒细胞，且细胞核中可检测到磷酸化AMPK。上述研究结果表明，中性粒细胞来源的MMP-8在结核病的免疫病理损伤中发挥关键作用，且可作为该感染性疾病宿主导向治疗的潜在靶点。