Drake, Li Y.

Local production of growth factors within the airway with autocrine/paracrine effects can promote features of asthma. Here, we show that glial-derived neurotrophic factor (GDNF) is a procontractile and proremodeling factor that contributes to allergen-induced airway hyperreactivity and tissue remodeling in a mouse model of asthma. Blocking GDNF signaling attenuates allergen-induced airway hyperreactivity and remodeling, suggesting a novel approach to alleviating structural and functional changes in the asthmatic airway.

Abstract Group 2 innate lymphoid cells (ILC2s) play crucial roles in type 2 immunity in the lungs and in the development of asthma pathology. While ILC2s are residents in mucosal tissues, they also circulate in peripheral blood. Evidence suggests that blood ILC2s can be used as an indirect but useful biomarker to monitor the activity of ILC2s in mucosal tissues, such as the lungs. To investigate both the innate immune response and the corresponding ILC2 cell levels in the peripheral blood of asthma patients, we collected peripheral blood mononuclear cells (PBMCs) from 11 adult patients with mild asthma (MA) and 12 adult healthy control (HC) subjects. The innate type 2 immune responses of PBMCs and the number of blood ILC2s were examined by in vitro culture and flow cytometry. We found that in response to IL-25 or IL-33 stimulation, PBMCs from MA subjects produced significant higher levels of IL-5 than PBMCs from HC subjects. However, there were no significant differences in ILC2 numbers or proportions between MA and HC groups. These results suggest that the function, but not the number, of blood ILC2s may serve as a general biomarker for human asthma.

Abstract Type 2 innate lymphoid cells (ILC2s) are part of a large family of ILCs that are important effector cells in innate immunity. Recent studies suggest that lung ILC2s play critical roles in host immunity against helminth infection and in maintaining tissue homeostasis after respiratory viral infection. However, little is known as to whether and how these cells influence adaptive immunity. Here we report that lung ILC2s enhanced proliferation of naïve CD4+ T cells and promoted production of T helper type 2 (Th2) cytokines including IL-4, IL-5 and IL-13. ILC2s regulated T cell function by direct contact through OX40/OX40L interaction. Furthermore, IL-4 produced by ILC2s when cultured with CD4+ T cells played an important role in Th2 cytokine upregulation. We further revealed that lung ILC2s promoted IgA, IgE, IgG1 and IgM antibody production by both B1 and B2 cells, and that this stimulatory effect of ILC2s was mediated at least in part by ILC2 production of cytokines IL-5 and IL-13. We conclude that ILC2s promote both T cell- and B cell-mediated immune responses and propose that ILC2s may play roles in regulating adaptive immunity in addition to their established roles in innate immunity.

Senescent cells can drive age-related tissue dysfunction partially via a senescence-associated secretory phenotype (SASP) involving proinflammatory and profibrotic factors. Cellular senescence has been associated with a structural and functional decline during normal lung aging and age-related diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Asthma in the elderly (AIE) represents a major healthcare burden. AIE is associated with bronchial airway hyperresponsiveness and remodeling, which involves increased cell proliferation and higher rates of fibrosis, and resistant to standard therapy. Airway smooth muscle (ASM) cells play a major role in asthma such as remodeling via modulation of inflammation and the extracellular matrix (ECM) environment. Whether senescent ASM cells accumulate in AIE and contribute to airway structural or functional changes is unknown. Lung tissues from elderly persons with asthma showed greater airway fibrosis compared with age-matched elderly persons with nonasthma and young age controls. Lung tissue or isolated ASM cells from elderly persons with asthma showed increased expression of multiple senescent markers including phospho-p53, p21, telomere-associated foci (TAF), as well as multiple SASP components. Senescence and SASP components were also increased with aging per se. These data highlight the presence of cellular senescence in AIE that may contribute to airway remodeling.