Emergency myelopoiesis contributes to immune cell exhaustion and pulmonary vascular remodelling.

Chunhua Fu, Yuanqing Lu, Mason A Williams, Mark L Brantly, Corey E Ventetuolo, Laurence M Morel, Borna Mehrad, Edward W Scott, Andrew J Bryant

British journal of pharmacology 2021 Jan

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Pulmonary hypertension (PH) secondary to chronic lung disease (World Health Organization Group 3 PH) is deadly, with lung transplant being the only available long-term treatment option. Myeloid-derived cells are known to affect progression of both pulmonary fibrosis and PH, although the mechanism of action is unknown. Therefore, we investigated the effect of myeloid cell proliferation induced by emergency myelopoiesis on development of PH and therapy directed against programmed death-ligand 1 (PD-L1), expressed by myeloid cells in prevention of pulmonary vascular remodelling. LysM.Cre-DTR ("mDTR") mice were injected with bleomycin (0.018 U·g-1 , i.p.) while receiving either vehicle or diphtheria toxin (DT; 100 ng, i.p.) to induce severe PH. Approximately 4 weeks after initiation of bleomycin protocol, right ventricular pressure measurements were performed and tissue samples collected for histologic assessment. In a separate experiment, DT-treated mice were given anti-PD-L1 antibody (αPD-L1; 500 μg, i.p.) preventive treatment before bleomycin administration. Mice undergoing induction of emergency myelopoiesis displayed more severe PH, right ventricular remodelling and pulmonary vascular muscularization compared to controls, without a change in lung fibrosis. This worsening of PH was associated with increased pulmonary myeloid-derived suppressor cell (MDSC), particularly polymorphonuclear MDSC (PMN-MDSC). Treatment with αPD-L1 normalized pulmonary pressures. PD-L1 expression was likewise found to be elevated on circulating PMN-MDSC from patients with interstitial lung disease and PH. PD-L1 is a viable therapeutic target in PH, acting through a signalling axis involving MDSC. This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc. © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Citation

Chunhua Fu, Yuanqing Lu, Mason A Williams, Mark L Brantly, Corey E Ventetuolo, Laurence M Morel, Borna Mehrad, Edward W Scott, Andrew J Bryant. Emergency myelopoiesis contributes to immune cell exhaustion and pulmonary vascular remodelling. British journal of pharmacology. 2021 Jan;178(1):187-202