ABSTRACT

Rationale Group 2 innate lymphoid cells (ILC2s) are important in asthma pathogenesis but their role in chronic obstructive pulmonary disease (COPD) has been controversial. COPD is associated with impaired function and expression of surfactant protein D (SP-D), a protective immune regulator in the lung.

Objectives We aimed to establish the pathogenic significance of ILC2s and their regulation by SP-D in COPD.

Methods Lung function, sputum and peripheral blood SP-D, immune cell and cytokine profile were evaluated in COPD and healthy subjects. Responsiveness to the air pollutant ozone (O3) was studied in COPD-like SP-D-/- and conditional SP-D expressor mouse models. The effects of recombinant SP-D on isolated ILC2 gene and protein expression were investigated in vitro.

Measurements and Main Results COPD patients with elevated sputum GATA3+ILC2s (the ILC2high group) showed significantly increased numbers of eosinophils, neutrophils and IL-17+ILC2s. The ILC2 counts in ILC2high (but not ILC2low) sputum samples correlated with lung function, airway inflammation and leakage of degraded SP-D into the circulation. SP-D deficiency in O3-exposed mice enhanced airway neutrophilia, promoted activation and RORγt and IL-17 expression by ILC2s in the lung. Recombinant SP-D suppressed both IL-13 and IL-17A in ILC2s in vitro. Adoptively transferred ILC2 induced neutrophilia in O3-exposed Rag2/γc-/- mice in an IL-17A dependent manner.

Conclusions IL-17A+ILC2s were associated with a mixed neutrophilic and eosinophilic inflammation in COPD sputum and drove O3-induced exacerbation of airway inflammation in a mouse model. SP-D directly inhibited IL-17A+ILC2s. Presence of IL-17A+ILC2s may predict COPD severity.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was funded by the Tobacco-Related Disease Research Program.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

IRB of University of California, Davis gave ethical approval for this work.

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Yes

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Footnotes

↵* Now at Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital

Support: T32ES007059 and T32HL007013 to C.H.F; R21AI116121 and TRDRP27IR-0053 to A.H.

Online Data Supplement: This article has an online data supplement, which is accessible from this issues table of contents online at www.atsjournals.org.

Data Availability

All data produced in the present work are available upon reasonable request to the authors.

ABBREVIATIONSCOPDChronic Obstructive Pulmonary DiseaseSP-DSurfactant Protein-DILCInnate Lymphoid CellILC1Group 1 Innate Lymphoid CellILC2Group 2 Innate Lymphoid CellILC3Group 3 Innate Lymphoid CellFEV1Forced Expiratory Volume in one secondFVCForced Vital CapacityGOLDGlobal Initiative for Chronic Obstructive Lung DiseasePFTPulmonary Function TestingmMRCModified Medical Research Council scaleCATCOPD Assessment TestMPMacrophage/monocyteLCLymphocyteNPNeutrophilEPEosinophilWTC57BL/6 Wild-typeBALBronchoalveolar LavageO3OzonePBSPhosphate-buffed SalinerSP-DMouse Recombinant SP-DSpO2Specific Oxygen