Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity

Abstract

Patients with asthma, a major public health problem, are at high risk for serious disease from influenza virus infection, but the pathogenic mechanisms by which influenza A causes airway disease and asthma are not fully known. We show here in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (TH2) cells and adaptive immunity. Instead, influenza infection induced AHR through a previously unknown pathway that required the interleukin 13 (IL-13)–IL-33 axis and cells of the non-T cell, non-B cell innate lymphoid type called ‘natural helper cells’. Infection with influenza A virus, which activates the NLRP3 inflammasome, resulted in much more production of IL-33 by alveolar macrophages, which in turn activated natural helper cells producing substantial IL-13.

Type-2 Innate Lymphoid Cells in Asthma and Allergy

“…The ILC family now includes ILC1 (predominantly IFN-g-expressing cells), ILC2 (predominantly IL-5-and IL-13-expressing cells), and ILC3 (predominantly IL-22-and IL-17-expressing cells) (3)(4)(5)(6). Due to their recent discovery, our knowledge of these cells is still rather rudimentary, but major roles are emerging for ILCs in protective immunity against parasitic helminths (ILC2) (7)(8)(9) and bacteria (ILC1 and ILC3) (10)(11)(12), and in autoimmune disorders (ILC1 and ILC3) (13), allergic disease (ILC2) (14)(15)(16), and obesity (17)(18)(19).…”

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

“…NH cells can produce large amounts of type-2 cytokines such as IL-5 and IL-13 in response to IL-33. Several groups have characterized populations of type-2 cytokine-producing ILCs associated with IL-33 mediate diseases in the lung [15][16][17][18][19][20][21] . However, it is unknown whether NH cells are involved in the observed corticosteroid sensitivity.…”

Innate Lymphoid Cells in Type 2 Immune Responses

“…A number of groups have demonstrated the role of ILC2 as key producers of type 2 cytokines in several different experimental lung inflammation models (Barlow et al 2012Bartemes et al 2012;Chang et al 2011;Kim et al 2012;Scanlon and McKenzie 2012;Walker and McKenzie 2013). The activation of ILC2 within lungs is very rapid, with high levels of IL-5 and IL-13 production within 12 h of exposure of mice to the fungal allergen Alternaria alternata (Bartemes et al 2012).…”

“…Chang et al (2011) showed that ILC2, activated by macrophagederived IL-33, were sufficient to drive influenza-induced airway hyperresponsiveness (AHR) in mice. This effect was mediated by ILC2-derived IL-13, since adoptive transfer of wild-type ILC2 into infected il13 -/-mice was sufficient to restore viral-induced AHR in these otherwise AHR-resistant mice (Chang et al 2011).…”

“…Chang et al (2011) showed that ILC2, activated by macrophagederived IL-33, were sufficient to drive influenza-induced airway hyperresponsiveness (AHR) in mice. This effect was mediated by ILC2-derived IL-13, since adoptive transfer of wild-type ILC2 into infected il13 -/-mice was sufficient to restore viral-induced AHR in these otherwise AHR-resistant mice (Chang et al 2011). Whilst the physiological role of ILC2 in human airway inflammation is not fully understood, ILC2 were shown to be elevated in nasal biopsies of chronic rhinosinusitis patients as compared to healthy controls (Mjosberg et al 2011) demonstrating an association of these cells with human disease.…”