STAT6 regulates natural helper cell proliferation during lung inflammation initiated byAlternaria

Abstract

Asthma exacerbations can be caused by a number of factors, including the fungal allergen Alternaria, which is specifically associated with severe and near-fatal attacks. The mechanisms that trigger lung responses are unclear and might vary between allergens. A comparison between Alternaria, Aspergillus, Candida, and house dust mite, all allergens in humans, showed that only Alternaria promoted immediate innate airway eosinophilia within 12 h of inhalation in nonsensitized mice. Alternaria, but not the other allergens, induced a rapid increase in airway levels of IL-33, accompanied by IL-33 receptor (IL-33R)-positive natural helper cell (NHC) production of IL-5 and IL-13. NHCs in the lung and bone marrow constitutively expressed transcription factors [GATA-3 and E26 transformation-specific sequence-1 (ETS-1)] that could allow for rapid induction of T helper type 2 (Th2) cytokines. Lung NHC numbers and proliferation (%Ki-67), but not IL-5 or GATA-3 expression, were significantly reduced in STAT6-deficient mice 3 days after one challenge with Alternaria. Alternaria induced NHC expression of the EGF receptor ligand amphiregulin (partially dependent on STAT6), as well as EGF receptor signaling in the airway epithelium. Finally, human peripheral blood NHCs (CRTH2(+)CD127(+) lineage-negative lymphocytes) from allergic individuals highly expressed GATA-3 and ETS-1, similar to lung NHCs in mice. In summary, Alternaria-induced lung NHC proliferation and expression of amphiregulin are regulated by STAT6. In addition, NHCs in mouse and humans are primed to express Th2 cytokines through constitutive expression of GATA-3 and ETS-1. Thus several transcription factor pathways (STAT6, GATA-3, and ETS-1) may contribute to NHC proliferation and Th2-type responses in Alternaria-induced asthma.

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

“…Other studies using the fungal allergen Alternaria have led to similar conclusions, whereby the induction of airway inflammation is heavily dependent on IL-33 signaling and mediated by activated ILC2s rather than Th2 cells [14,15]. ILC2s were shown to have the capacity to enhance differentiation of naive CD4 + T cells to a Th2 phenotype while inhibiting Th1 differentiation in a contactdependent manner [16,17].…”

“…responses [12][13][14][15]18]. However, the contribution of ILC2s in HDM-induced allergic inflammation and the mechanisms that link ILC2 activation and the adaptive immune system are not completely understood.…”

Group 2 Innate Lymphoid Cells in Health and Disease

“…For example, IL-33-induced ILC2s that produce IL-13 contributed to the development of AHR in multiple murine asthma models in the absence of CD4 þ T cells (Bartemes et al 2012;Beamer et al 2012;Doherty et al 2012;Kim et al 2012;Salmond et al 2012).…”

Emerging roles of innate lymphoid cells in inflammatory diseases: Clinical implications

“…7 When stimulated by epithelial cell-derived innate mediators, that is IL-25, IL-33, thymic stromal lymphopoietin (TSLP), or prostaglandin D2 (PGD2), these cells rapidly expand and secrete large amounts of IL-5, IL-13, and, under certain conditions, also IL-4. 2 Presently, the pivotal role of ILC2s in allergic airway inflammation is well established in various murine models.…”

“…In humans, ILC2s were found in healthy lung parenchyma and bronchoalveolar lavage (BAL) fluid from patients who underwent lung transplantation, in nasal polyps, and at low numbers in peripheral blood. [7][8][9] By production of cytokines and via direct interaction with myeloid and Th2 cells, they promote mucus production, eosinophilia, and accumulation of mast cells in allergic diseases. 10 …”