The role of airway epithelial cells and innate immune cells in chronic respiratory disease

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.

Figure 1. Adaptive and innate immune responses in chronic respiratory disease

a | Environm ental stimuli — suchas respiratory viruses, allergens and/or tobacco smoke — may act on genetically susceptible individuals to lead to an altered immune response, end-organ dysfunction and chronic inflammatory disease. b | An altered adaptive immune response involves antigen-presenting cells, primarily dendritic cells (DCs), that process and present antigens to memory B cells and T cells that drive the activation of effector immune cells (such as eosinophils and mast cells). Additional T cell subsets that regulate the adaptive immune response include T helper 17 (T_H17) cells, T_H9 cells and regulatory T cells (not shown). Alternatively, an altered innate immune response can involve airway epithelial cells (AECs) that activate innate immune cells, such as invariant natural killer T (iNKT) cells, M2 macrophages and innate lymphoid cells (ILCs). c | Effector cells or innate immune cells then produce type 2 cytokines — for example, interleukin-4 (IL-4) and IL-13 — that act on end-organ cells, especially AECs, to produce excess mucus, and on airway smooth muscle cells (ASMCs) to manifest airway hyperreactivity, which, to varying degrees, are both characteristic of patients with asthma and chronic obstructive pulmonary disease.

Figure 2. PRR pathways in AECs leading to airway disease

Allergens such as Der-p2 derived from the house dust mite (HDM) Dermatophagoides farinae and fibrinogen cleavage products (FCPs) that are generated by proteases from the fungus Aspergillus oryzae can act as ligands for the Toll-like receptor 4 (TLR4) complex. The activation of TLR4-dependent signalling leads to an allergic response that is characterized by type 2 cytokine production. Alternatively, viral infection can induce the activation of several additional TLRs (such as TLR3, TLR7, TLR8 and TLR9) in the endosome and can also activate RIG-I-like receptors (RLRs) — such as melanoma differ entiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I (RIG-I) — in the cytosol. In each case, activation leads to downstream signalling with the eventual stimulation of transcription factors in the nucleus and consequent expression of the indicated cytokines and interferon (IFN)-stimulated genes (ISGs). dsRNA, double-stranded RNA; IL, interleukin; IRF, IFN-regulatory factor; MAVS, mitochondrial antiviral signalling protein; MD2, myeloid differentiation factor 2; MYD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-κB; ssRNA, single-stranded RNA; TNF, tumour necrosis factor; TRIF, TIR domain-containing adaptor protein inducing IFNβ.

Figure 3. Innate immune responses of AECs drive airway disease

Respiratory viral infection (which is perhaps enhanced by exposure to allergens or tobacco smoke) leads to an expansion of airway progenitor epithelial cells (APECs), which are a subset of integrin α6 (ITGA6)-expressing basal cells in humans or secretory cells expressing SCGB1A1 (also known as uteroglobin) in mice that are programmed for increased interleukin-33 (IL-33) expression. Subsequent epithelial ‘danger’ signals stimulate ATP-regulated release of IL-33 that acts on innate immune cells in the lungs — for example, type 2 innate lymphoid cells (ILC2s) and invariant natural killer T (iNKT) cells, which can interact with M2-like macrophages to stimulate IL-13 production. IL-13 then induces IL-13 receptor (IL-13R) signalling to stimulate calcium-activated chloride channel regulator 1 (CLCA1) expression and mitogen-activated protein kinase 13 (MAPK13)-dependent signalling, which activate expression of MUC5AC (which encodes mucin 5AC) and, consequently, lead to airway mucous cell activation and mucus formation. Figure modified with permission from the American Society for Clinical Investigation (REF. 16).

Figure 4. Innate immune cells in post-viral airway disease

a | Viral infection drives airway epithelial cell (AEC) release of interleukin-33 (IL-33) and the subse quent activation of invariant NKT (iNKT) cells that express an invariant Vα 14-Jα 18 T cell receptor (TCR) that recognizes glycolipids presented on CD1d molecules by lung monocytes and M2 macrophages. These signals lead to increased expression of the IL-13 receptor (IL-13R), and production of IL-13 that facilitates a positive feedback loop to amplify IL-13 production and alternative activation of monocytes and macrophages. Alternatively activated monocytes and macrophages are marked by epidermal arachidonate 12-lipoxygenase (ALOX12E), arginase 1 (ARG1), chitinase-like protein 3 (CHIL3), CHIL4, FIZZ1 (also known as resistin-like molecule-α) and matrix metalloproteinase 12 (MMP12) expression in mice, and by ALOX15, CD163, CD206, chitotriosidase 1 (CHIT1) and MMP12 expression in humans. AEC release of IL-33 may also stimulate type 2 innate lymphoid cells (ILC2s), as well as effector granulocytes (such as eosinophils, mast cells and basophils; not shown), to produce IL-13. b | Viral infection also stimulates interferon-β (IFNβ)-dependent and CD49d⁺ neutrophil-dependent upregulation of the high-affinity Fc receptor for IgE (FcεRI) expression on resident lung dendritic cells (DCs). In turn, FcεRI activation by viral antigens and IgE leads to the production of CC-chemokine ligand 28 (CCL28) and the recruitment of CC-chemokine receptor 10 (CCR10)-expressing IL-13-producing T helper 2 (T_H2) cells to the lungs.