Ingram Jennifer L, McQuade Victoria L, Weiss Jasmine, Womble Jack T, Ihrie Mark D, Zhao Karen, Francisco Dave, Theriot Barbara, May Katelynn, Kim Haein, McCravy Matthew, Sauler Maor, Lugogo Njira L, Sunday Mary E, Everitt Jeffrey, Walker Julia K L, Tighe Robert M, Kraft Monica, Que Loretta G
Department of Medicine, Duke University Medical Center, Durham, NC.
Department of Medicine, Duke University Medical Center, Durham, NC.
J Allergy Clin Immunol. 2025 Mar;155(3):819-833.e10. doi: 10.1016/j.jaci.2024.10.039. Epub 2024 Nov 22.
Airway tissue eosinophilia can be an observed feature of obesity-associated type 2 (T2) asthma, but the processes mediating this inflammation are unknown.
To investigate a process whereby leptin, an adipokine elevated in obesity, potentiates pulmonary eosinophilia and eotaxin production by airway fibroblasts in T2 asthma.
We assessed associations between body mass index and airway eosinophilia as well as leptin and eotaxin production in 82 participants with asthma, 37 of whom exhibited obesity. Cultured human airway fibroblasts and mouse models of chronic allergic airway disease were used to evaluate leptin's effect on eotaxin production and lung eosinophilia. The role of IL-13 receptor alpha 2 (IL-13Rα2) in mediating these processes was examined using specific neutralizing antibodies in vitro.
In participants with T2 asthma and obesity, we observed that airway tissue eosinophilia did not associate with traditional T2 inflammation metrics such as peripheral and/or bronchoalveolar lavage fluid eosinophil counts or with fractional exhaled nitric oxide. Alternatively, we observed elevated bronchoalveolar lavage fluid leptin and eotaxin-1 levels. In airway fibroblasts from participants with asthma, leptin augmented IL-13-induced eotaxin-1 and eotaxin-3 production and IL13RA2 expression. In mice, elevated leptin promoted airway IL-13Rα2 and eotaxin production by lung fibroblasts and lung tissue eosinophilia following chronic house dust mite allergen exposure. Inhibition of IL-13Rα2 reduced combined leptin and IL-13-stimulated eotaxin secretion by human airway fibroblasts.
We identified a potential association explaining airway tissue eosinophil retention in obesity-associated T2 asthma through leptin-mediated enhancement of IL-13-induced eosinophil chemokine production by airway fibroblasts, a process requiring IL-13Rα2.
气道组织嗜酸性粒细胞增多是肥胖相关2型（T2）哮喘的一个可观察到的特征，但介导这种炎症的过程尚不清楚。
研究肥胖时升高的脂肪因子瘦素增强T2哮喘患者气道成纤维细胞肺嗜酸性粒细胞增多和嗜酸性粒细胞趋化因子产生的过程。
我们评估了82例哮喘患者的体重指数与气道嗜酸性粒细胞增多以及瘦素与嗜酸性粒细胞趋化因子产生之间的关联，其中37例患有肥胖症。使用培养的人气道成纤维细胞和慢性过敏性气道疾病小鼠模型来评估瘦素对嗜酸性粒细胞趋化因子产生和肺嗜酸性粒细胞增多的影响。在体外使用特异性中和抗体检查IL-13受体α2（IL-13Rα2）在介导这些过程中的作用。
在患有T2哮喘和肥胖症的参与者中，我们观察到气道组织嗜酸性粒细胞增多与传统的T2炎症指标（如外周血和/或支气管肺泡灌洗液嗜酸性粒细胞计数）或呼出一氧化氮分数无关。相反，我们观察到支气管肺泡灌洗液中瘦素和嗜酸性粒细胞趋化因子-1水平升高。在哮喘患者的气道成纤维细胞中，瘦素增强了IL-13诱导的嗜酸性粒细胞趋化因子-1和嗜酸性粒细胞趋化因子-3的产生以及IL13RA2的表达。在小鼠中，慢性屋尘螨过敏原暴露后，升高的瘦素促进了肺成纤维细胞气道IL-13Rα2和嗜酸性粒细胞趋化因子的产生以及肺组织嗜酸性粒细胞增多。抑制IL-13Rα2可减少瘦素和IL-13联合刺激的人气道成纤维细胞嗜酸性粒细胞趋化因子分泌。
我们确定了一种潜在的关联，即通过瘦素介导增强气道成纤维细胞IL-13诱导的嗜酸性粒细胞趋化因子产生来解释肥胖相关T2哮喘中气道组织嗜酸性粒细胞的滞留，这一过程需要IL-13Rα2。
