Effects of Air Pollution on Lung Innate Lymphoid Cells: Review of In Vitro and In Vivo Experimental Studies

Abstract

Outdoor air pollution is associated with respiratory infections and allergies, yet the role of innate lymphoid cells (ILCs) in pathogen containment and airway hyperresponsiveness relevant to effects of air pollutants on ILCs is poorly understood. We conducted a systematic review to evaluate the available evidence on the effect of outdoor air pollutants on the lung type 1 (ILC1) and type 2 ILCs (ILC2) subsets. We searched five electronic databases (up to Dec 2018) for studies on the effect of carbon monoxide (CO), sulfur dioxide (SO₂), nitrogen dioxide (NO₂), diesel exhaust particles (DEP), ozone (O₃), and particulate matter (PM) on respiratory ILCs. Of 2209 identified citations, 22 full-text papers were assessed for eligibility, and 12 articles describing experimental studies performed in murine strains (9) and on human blood cells (3) were finally selected. Overall, these studies showed that exposure to PM, DEP, and high doses of O₃ resulted in a reduction of interferon gamma (IFN-γ) production and cytotoxicity of ILC1. These pollutants and carbon nanotubes stimulate lung ILC2s, produce high levels of interleukin (IL)-5 and IL-13, and induce airway hyperresponsiveness. These findings highlight potential mechanisms by which human ILCs react to air pollution that increase the susceptibility to infections and allergies.

Keywords: ILC; air pollutants; airway hyperresponsiveness; lung innate lymphoid cells.

Figure 1

Summarizes the understanding of innate lymphoid cell (ILC) types, activation pathways and functions. Innate lymphoid cells are derived from a common lymphoid progenitor, have a lymphoid morphology, and lack antigen-specific receptors. Based upon the transcription factors needed for their development and the cytokines they produce, ILCs are divided in three groups which mainly populate barrier surfaces. ILC1 includes classical natural killer (NK) and non-NK cells and depends on the transcription factor T-bet. ILC2 depends on the transcription factors GATA3 and RORα. ILC3 requires the transcription factor ROR-γt and comprises a heterogeneous subset of cells. After external antigen contact, respiratory epithelial cells and classical innate immune cells produce several cytokines which stimulate different ILCs groups. IL-12, IL-15, IL-18 prime ILC1s to produce IFN-γ and other cytokines involved in microbe elimination, Th1 activation, and tumor eradication. ILC2s are activated by IL-4, prostaglandin D2 (PGD2), IL-33 and IL-25 to produce amphiregulin involved in tissue repair, IL-5 to recruit eosinophils, and IL-13 to stimulate mucus production by epithelial cells. ILC3s are primed by IL-18, IL-23, and IL-1β to produce principally IL-17 and IL-22 which participate in lymphoid tissue formation, Th cell regulation, B cell activation, and epithelium activation and repair. EC, epithelial cell; MØ, macrophage; DC, dendritic cell; PGD2, prostaglandin D2; TSLP, Thymic Stromal Lymphopoietin.

Figure 2

Flow diagram of study selection.