Abstract
Allergic asthma and obesity are the leading health problems in the world. Many studies have shown that obesity is a risk factor of development of asthma. However, the underlying mechanism has not been well established. In this study, we demonstrate that leptin, an adipokine elevated in obese individuals, promoted proliferation and survival of pro-allergic type 2 helper T cells and group 2 innate lymphoid cells and production of type 2 cytokines, which together contribute to allergic responses. Leptin activates mTORC1, MAPK, and STAT3 pathways in TH2 cells. The effects of leptin on TH2 cell proliferation, survival, and cytokine production are dependent on the mTORC1 and MAPK pathways as revealed by specific inhibitors. In vivo, leptin-deficiency led to attenuated experimental allergic airway inflammation. Our results thus support that obesity-associated elevation of leptin contributes to the increased susceptibility of asthma via modulation of pro-allergic lymphocyte responses.
Highlights
Allergic asthma, one of the leading health problems, affects 300 million people worldwide and leads to ϳ250,000 deaths per year [1]
Leptin-deficiency Impairs Type 2 Immune Responses and Attenuates Allergic Airway Inflammation—To define the role of leptin in allergic responses, we utilized an experimental allergic asthma model induced by papain, a well-characterized protease-based allergen involved in human occupational allergic airway disease [29, 30], which is through induction of cytokines
ObϪ/Ϫ mice had significantly decreased infiltrates of eosinophils and lymphocytes in the bronchoalveolar lavage fluids (BALFs) compared with WT mice (Fig. 1B), whereas unchallenged ObϪ/Ϫ mice had only a few eosinophils and lymphocytes in the BALFs that are comparable with unchallenged WT mice
Summary
One of the leading health problems, affects 300 million people worldwide and leads to ϳ250,000 deaths per year (as of 2009) [1]. In addition to TH cells, group 2 innate lymphocytes (ILC2s), a recently defined subset of innate lymphocytes, were shown to play a key role in airway inflammation through secretion of the type 2 cytokines, IL-5, IL-13, and IL-9 (10 –14). IL-13 and TGF-, released by inflammatory cells, directly act on pulmonary epithelial and muscle cells and promote their proliferation, resulting in airway tissue remodeling and dysfunction [3]. Adipose tissue is an active endocrine organ secreting adipokines (such as leptin and adiponectin) and cytokines (such as IL-6, IL-8, TNF␣) These mediators regulate systemic metabolism and is implicated in the regulation of immune responses. Leptin is involved in the activation, differentiation, proliferation and function of immune cells, such as macrophages and NK cells Our results demonstrate a pathogenic role of leptin in asthmatic reactions
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