HMGB1 and chronic obstructive pulmonary disease: TLR4 and TLR9 are critical PPRs involved in COPD pathogenesis.42–44 TLR4 recognises exogenous ligands (such as lipopolysaccharide), respiratory syncytial virus fusion protein, and endogenous ligands like heat shock proteins (HSP60, HSP70) and high mobility group box 1 (HMGB1), whereas TLR9 specialises in the detection of unmethylated CpG motifs prevalent in bacterial and viral DNA, as well as in human mtDNA.45 cGAS is a crucial innate immune sensor that detects cytoplasmic DNA from pathogens or cellular injury.