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. 2025 Mar;155(3):819-833.e10.
doi: 10.1016/j.jaci.2024.10.039. Epub 2024 Nov 22.

Leptin augments IL-13-induced airway eotaxins and submucosal eosinophilia in obesity-associated asthma

Jennifer L Ingram  1 , Victoria L McQuade  2 , Jasmine Weiss  3 , Jack T Womble  2 , Mark D Ihrie  2 , Karen Zhao  2 , Dave Francisco  4 , Barbara Theriot  5 , Katelynn May  2 , Haein Kim  2 , Matthew McCravy  2 , Maor Sauler  6 , Njira L Lugogo  7 , Mary E Sunday  8 , Jeffrey Everitt  8 , Julia K L Walker  9 , Robert M Tighe  2 , Monica Kraft  4 , Loretta G Que  2
Affiliations

Leptin augments IL-13-induced airway eotaxins and submucosal eosinophilia in obesity-associated asthma

Jennifer L Ingram et al. J Allergy Clin Immunol. 2025 Mar.

Abstract

Background: Airway tissue eosinophilia can be an observed feature of obesity-associated type 2 (T2) asthma, but the processes mediating this inflammation are unknown.

Objective: To investigate a process whereby leptin, an adipokine elevated in obesity, potentiates pulmonary eosinophilia and eotaxin production by airway fibroblasts in T2 asthma.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: IL-13Rα2; T2 asthma; airway fibroblast; eosinophils; eotaxin; leptin; obesity.

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Conflict of interest statement

Disclosure statement This study was supported by the National Institutes of Health (grant no. R01HL130234 to J.L.I., grant nos. R01HL086887 and R01HL153641 to L.G.Q., grant nos. P01HL108793, R01HL064619, and SCCOR HL-05-009 to M.K., and grant nos. R01ES034350 and R01ES027574 to R.M.T.) and by the American Lung Association/American Academy of Allergy, Asthma & Immunology Allergic Respiratory Disease Award (to J.L.I.). Disclosure of potential conflict of interest: J. Weiss founded iDream Enterprise LLC and Let’s Diversifi PBLLC. R. M. Tighe received grants from Genentech and Boehringer Ingelheim; and completed a consulting relationship with Proctor & Gamble. J. L. Ingram received a grant from Sanofi/Regeneron. L. G. Que received grants from Sanofi/Regeneron and Boehringer Ingelheim. The rest of the authors declare that they have no relevant conflicts of interest.

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