COPD Monocyte-derived macrophages display hallmarks of senescence

Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition, associated with accelerated lung aging. Immune cells in aging diseases display features of senescence (immunosenescence) and chronic inflammation (inflammaging). COPD macrophages are more pro-inflammatory and have defective phagocytic function, but features of senescence in COPD macrophages is not well studied. Aim: To examine expression of senescence markers in macrophages from healthy and COPD subjects, in the presence and absence of oxidative stress (H₂O₂). Methods: Peripheral blood monocytes were isolated from age-matched non-smokers (NS) (n=9) and COPD patients (n=12) and then cultured in GM-CSF for 12 days to generate monocyte-derived macrophages (MDM). MDM were then treated with ±200µM H₂O₂ for 48h and expression of senescence markers was measured using qPCR. Results: At baseline, COPD MDM have increased expression of senescence markers p21CIP1 (2-fold, p>0.05), p27 (2.6-fold, p<0.05) and reduced anti-aging molecule, sirtuin (SIRT)6 (49%, p<0.05) and increased expression of senescence associated secretory phenotype (SASP) factors interleukin (IL)6 (50-fold, p<0.05) and CXCL8 (127-fold, p<0.01), compared to age-matched MDM from NS. In the presence of oxidative stress (H₂O₂), COPD MDM have further increased expression of p21CIP1 (2-fold, p<0.05), p27 (25%, p>0.05), IL6 (8-fold, p<0.05), CXCL8 (10-fold, p<0.01) and reduced SIRT1 (23%, p>0.05) and SIRT6 (61%, p<0.05), compared to age-matched NS. Conclusion: COPD MDM have elevated expression of senescence and SASP markers compared to healthy MDM and are more susceptible to oxidative stress induced senescence. This maybe associated with the altered macrophage phenotype in COPD.