Neutrophil hyperinflammation in uncontrolled DM drives tissue destruction in human pulmonary TB

Neutrophilia and systemic hyperinflammation are present in diabetic-tuberculosis (DMTB) patients but how diabetes worsens TB pathology is unclear. This study determines neutrophil function, human protease secretion and expression <italic>in vitro</italic> and in patients to unravel the mechanisms. Sputum and plasma from 30 pulmonary TB and 30DMTB patients (HbA1c>8%) were analysed for proteases by luminex bead array. Lung pathology was assessed by CXR. Whole blood and neutrophil gene expression were examined through bulk- and single-cell RNA sequencing. Neutrophils from DM patients and healthy controls (HC) were infected with <italic>Mycobacterium tuberculosis</italic> (<italic>M.tb</italic>). Reactive oxygen species (ROS) was assessed by chemiluminescence and intracellular signalling pathways by western blot. Relative to TB patients, DMTB patients had increased lung pathology, neutrophil-associated MMP-8, -9, NGAL and IL-8 in the sputum, and MMP mediated collagen and gelatin degradation activities. RNA sequencing demonstrated increased neutrophil fraction in DMTB patients with functional enrichment in extracellular matrix degradation, TNFα and RAGE pathways. This was validated by increased TNFR, NF-kB and RAGE receptor proteins from <italic>M.tb</italic>-infected DM neutrophils. <italic>M.tb</italic>-infected DM neutrophils had higher ROS and MMP-9 release, with RAGE inhibition suppressed ROS and MMP-8 secretion. Altogether our data show neutrophil hyperinflammation drives tissue destruction in DMTB. <fig><object-id>erj;64/suppl_68/PA648/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>