Mechanism of impaired monocyte responses in patients with Chronic Obstructive Pulmonary Disease (COPD)

Author information

Synat Keam^1,2, Dino B.A Tan^1,2, Jesse David Armitage^1,2, Dave Singh³, Yuben Moodley^1,2,4

¹Center for Respiratory Health, School of Biomedical Sciences, University of Western Australia, WA, Australia

²Stem Cell Unit, Institute for Respiratory Health, University of Western Australia, WA, Australia
³Respiratory Research Group, University of Manchester, United Kingdom

Abstract

Background
COPD is a chronic respiratory inflammatory disease and patients are highly susceptible to respiratory infections. This suggests a faulty host-immune system such as impaired phagocytic function and increases the risk of acute exacerbation events, which can be life‑threatening.

Aim(s)
To understand the underlying mechanisms, we aimed to determine:

1. The level of phagocytosis and TLR2 / 4 expression by monocytes.

2. The level of CTLA-4 and PD-1 on T cell subsets.

3. If phagocytosis can be improved by CTLA-4 or PD-1 blockade.

Method(s)
Cryopreserved cells of excised lung samples from COPD patients (n=10) and non-COPD controls (n=10) were cultured with NTHi pre-labelled with pHrodo™ with or without CTLA-4 or PD-1 blockade for two hours and phagocytosis was assessed by flow cytometry. Cells were also immunophenotyped for the expression of TLR-2 / 4 and inhibitory receptors (PD-1 and CTLA-4) on CD4+ T cells, and regulatory T cells (Tregs) using flow cytometry.

Result(s)
Phagocytosis of pHrodo™-NTHi by monocytes was lower in COPD patients than non‑COPD controls (p=0.01). TLR-4 expression on monocytes was significantly reduced in COPD patients than non‑COPD controls (p=0.01). Additionally, TLR‑2 expression on monocytes positively correlated with phagocytosis of NTHi by monocytes (r=0.76, p=0.01). Frequencies of CD4+ T cells and Tregs expressing intracellular CTLA-4 and PD-1 did not differ between COPD patients and non‑COPD controls. Interestingly, intracellular CTLA-4 on CD4+ T cell and Tregs negatively correlated with phagocytosis of NTHi by monocytes (r=-0.89, p=0.001 and r=-0.64, p=0.04). Increased phagocytosis of NTHi by monocyte after CTLA-4 and PD-1 blockade was seen only in a proportion of COPD and non-COPD subjects.

Summary and conclusions

Overall, CTLA-4 blockade increased phagocytosis in a proportion of COPD patients. Impaired TLR-2 / 4 expression on monocytes may present a more direct cause of impaired phagocytosis and thus provide a therapeutic target to improve anti-bacterial responses in COPD.

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