Dept. of Medicine, Univ. of California San Diego, Biomedical Sciences Bldg., La Jolla, CA 92093-0635, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 Oct 1;303(7):L577-88. doi: 10.1152/ajplung.00174.2012. Epub 2012 Aug 3.
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.
哮喘恶化可由多种因素引起，包括真菌过敏原链格孢，它与严重和近乎致命的发作特别相关。触发肺部反应的机制尚不清楚，并且可能在过敏原之间有所不同。对链格孢、曲霉菌、假丝酵母和屋尘螨（人类的所有过敏原）进行的比较表明，只有链格孢在吸入非致敏小鼠 12 小时内促进了即时先天气道嗜酸性粒细胞增多。与其他过敏原不同，链格孢诱导气道中白细胞介素 33（IL-33）水平迅速增加，同时伴有 IL-33 受体（IL-33R）阳性天然辅助细胞（NHC）产生 IL-5 和 IL-13。肺和骨髓中的 NHC 组成性表达转录因子[GATA-3 和 E26 转化特异性序列-1（ETS-1）]，这可能允许快速诱导辅助性 T 细胞 2（Th2）细胞因子。在接受链格孢一次挑战后 3 天，STAT6 缺陷小鼠的肺 NHC 数量和增殖（%Ki-67），但不是 IL-5 或 GATA-3 的表达，显著减少。链格孢诱导 NHC 表达表皮生长因子受体配体 Amphiregulin（部分依赖于 STAT6），以及气道上皮细胞中的 EGF 受体信号。最后，来自过敏个体的人外周血 NHC（CRTH2（+）CD127（+）谱系阴性淋巴细胞）高度表达 GATA-3 和 ETS-1，类似于小鼠肺 NHC。总之，链格孢诱导的肺 NHC 增殖和 Amphiregulin 表达受 STAT6 调节。此外，通过 GATA-3 和 ETS-1 的组成性表达，小鼠和人类的 NHC 被预先设定为表达 Th2 细胞因子。因此，几种转录因子途径（STAT6、GATA-3 和 ETS-1）可能有助于链格孢诱导的哮喘中 NHC 增殖和 Th2 型反应。
