Key Points
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The innate immune system is crucial for host defence but is also implicated in driving inflammatory diseases of the lower respiratory tract, such as asthma and chronic obstructive pulmonary disease (COPD). This mechanism of pathogenesis is distinct from the conventional view that the adaptive immune system is responsible for chronic inflammatory disease.
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Airway epithelial cells that line the mucosal surface of the lower airways and various immune cell populations (such as natural killer T cells, macrophages and innate lymphoid cells) actively participate in both host defence and disease in the lungs.
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Airway epithelial cells are equipped with pattern recognition receptors (PRRs) to trigger the innate immune response to microbial pathogens, although the specific subsets of PRRs and the types of airway epithelial cells (for example, ciliated cells, mucous cells, secretory cells and basal cells) that express these receptors still need to be better defined. A key effect of PRR activation is the downstream production of interferons (IFNs) and expression of IFN-stimulated genes, and precisely how this contributes to host defence (particularly against respiratory viruses) is currently under study.
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Airway epithelial cells are also capable of expansion as a special progenitor or stem cell niche, and this subpopulation of airway progenitor epithelial cells has the capacity for the long-term production of cytokines — for example, interleukin-33 (IL-33) — that can drive type 2 immune responses and consequent airway disease.
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Innate immune cells can respond to cytokine signals with a type 2 immune response (typified by IL-13 production) that in turn causes remodelling of the airway epithelium to a disease phenotype — for example, mucous cell metaplasia. The precise subsets of innate immune cells that are involved still need to be better defined in humans with chronic airway disease. Similarly, the role of granulocyte populations and the link to non-type 2 cytokine (for example, IL-17) production and consequent airway disease also needs further characterization.
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New therapeutics aimed at correcting excessive innate immune responses have reached the stage of clinical trials for asthma and COPD. Current trials focus particularly on targeting type 2 cytokines (for example, IL-13) to attenuate chronic airway disease. These approaches are challenged by the need to develop biomarkers that can stratify patients and thereby identify patient subsets that might benefit from specific immunotherapies.
Abstract
An abnormal immune response to environmental agents is generally thought to be responsible for causing chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Based on studies of experimental models and human subjects, there is increasing evidence that the response of the innate immune system is crucial for the development of this type of airway disease. Airway epithelial cells and innate immune cells represent key components of the pathogenesis of chronic airway disease and are emerging targets for new therapies. In this Review, we summarize the innate immune mechanisms by which airway epithelial cells and innate immune cells regulate the development of chronic respiratory diseases. We also explain how these pathways are being targeted in the clinic to treat patients with these diseases.
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Acknowledgements
The authors sincerely thank the members of the Holtzman laboratory and their collaborators for generating the research perspective that underlies this review. Research on this topic in the laboratory of M.J.H. was supported by grants from the US National Institutes of Health (U19-AI070489, R01-HL121791, U01-AI095776, P01-HL29594 and P50-HL107183).
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M.J.H. is the principal investigator for research grants to Washington University from Hoffman-LaRoche and Forest Laboratories. D.E.B, J.A.-B. and X.W. declare no competing interests.
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Glossary
- Airway epithelial cells
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(AECs). The AECs that line the airways include ciliated, mucous, secretory and basal cell types. The AECs also line the alveoli and include type 1 and type 2 epithelial cells.
- Pattern recognition receptors
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(PRRs). These receptors are a key part of the initial activation step for innate immune cells. They recognize pathogen-associated molecular patterns that are associated with microbial pathogens, as well as damage-associated molecular patterns associated with cell damage.
- Airway progenitor epithelial cell
-
(APEC). These cells are able to proliferate and then differentiate into different airway epithelial cell subsets.
- Innate lymphoid cells
-
(ILCs). A group of cells that are similar in size and shape to lymphocytes but that do not express typical markers of T cells, B cells, natural killer (NK) cells, NKT cells or the granulocyte lineage. A current paradigm divides ILCs into three groups: ILC1s that produce interferon-γ; ILC2s that produce interleukin-5 (IL-5) and IL-13; and ILC3s that produce IL-17 and/or IL-22 and are also known as ILC17s and ILC22s.
- M2-type macrophage activation
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An immune response that involves the alternative activation of macrophages and monocytes, and is characterized by a gene expression profile that is distinctive of stimulation by interleukin-4 (IL-4) or IL-13. There is still some uncertainty over the best markers for interferon-γ-driven classical activation of M1-type macrophages versus IL-4- and IL-13-driven alternative activation of M2-type macrophages, but the concept remains useful in mouse models of disease and is a starting point for defining macrophage responses in human disease.
- Periostin
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A ligand for the αVβ3 and αVβ5 integrins that supports epithelial cell migration and adhesion.
- Mutein
-
A mutant form of a protein.
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Holtzman, M., Byers, D., Alexander-Brett, J. et al. The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol 14, 686–698 (2014). https://doi.org/10.1038/nri3739
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DOI: https://doi.org/10.1038/nri3739
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