IL-21 Rescues the Defect of IL-10-Producing Regulatory B Cells and Improves Allergic Asthma in DOCK8 Deficient Mice

Mutations in human DOCK8 cause a combined immunodeficiency syndrome characterized by allergic diseases such as asthma and food allergy. However, the underlying mechanism is unclear. Regulatory B (Breg) cells that produce IL-10 exert potent immunosuppressive functions in patients with allergic and autoimmune disorders. DOCK8-deficient B cells show diminished responses to TLR9 signaling, suggesting a possible defect in IL-10-producing Breg cells in those with DOCK8 deficiency, which may contribute to allergies. Here, we isolated peripheral blood mononuclear cells from DOCK8-deficient patients and generated a Dock8 KO mouse model to study the effect of DOCK8 deficiency on Breg cells. DOCK8-deficient patients and Dock8 KO mice harbored quantitative and qualitative defects in IL-10-producing Breg cells; these defects were caused by abnormal Dock8-/- CD4+ T cells. We found that recombinant murine (rm)IL-21 restored the function of Bregs both in vitro and in Dock8 KO mice, leading to reduced inflammatory cell infiltration of the lungs in a murine asthma model. Overall, the results provide new insight into the potential design of Breg-based or IL-21-based therapeutic strategies for allergic diseases, including asthma associated with DOCK8 deficiency.

RAGE mediates airway inflammation via the HDAC1 pathway in a toluene diisocyanate-induced murine asthma model

BackgroundExposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma; however, the mechanism is not clear. Epigenetic alterations of histone deacetylase (HDAC) are associated with allergic asthma. However, its effect in TDI-induced asthma is not known. The purpose of this study was to determine the role of RAGE and HDAC1 in the regulation of airway inflammation using a TDI-induced asthma model.MethodsBALB/c mice were sensitized, and challenged by TDI to establish murine asthma models. FPS-ZM1 (RAGE inhibitor), JNJ-26482585 and romidepsin (HDAC inhibitor) were given intraperitoneally before each challenge. The human bronchial epithelial cell line 16HBE was stimulated by TDI-human serum albumin (TDI-HSA) in vitro. RAGE knockdown cells were constructed and evaluated, and MK2006 (AKT inhibitor) was used in in vitro experiments.ResultsIn the TDI-induced asthmatic mice, airway reactivity, the level of Th2 cytokines in lymph supernatant, IgE, airway inflammation, and goblet cell metaplasia were all significantly increased. The increases were suppressed by FPS-ZM1, JNJ-26482585, and romidepsin. The expression of HDAC1, RAGE, and p-AKT/t-AKT was also upregulated in TDI-induced asthmatic mice, and the expressions were attenuated by FPS-ZM1. Knockdown of RAGE attenuated the upregulation of HDAC1 and phospho-AKT (p-AKT) in 16HBE cells stimulated by TDI-HSA. Treatment with the AKT inhibitor MK2006 suppressed TDI-induced HDAC1 expression. ConclusionRAGE mediates airway inflammation in a TDI-induced murine asthma model, partly via the HDAC1 pathway. Key words: Toluene diisocyanate, asthma, histone deacetylase 1, advanced glycosylation end product receptor

Therapeutic Efficacy of Curcumin Enhanced by Microscale Discoidal Polymeric Particles in a Murine Asthma Model

Curcumin is considered a potential anti-asthmatic agent owing to its anti-inflammatory properties. The objective of the present study was to prepare curcumin-containing poly(lactic-co-glycolic acid)-based microscale discoidal polymeric particles (Cur-PLGA-DPPs) and evaluate their anti-asthmatic properties using a murine asthma model. Cur-PLGA-DPPs were prepared using a top-down fabrication method. The prepared Cur-PLGA-DPPs had a mean particle size of 2.5 ± 0.4 μm and a zeta potential value of −34.6 ± 4.8 mV. Ex vivo biodistribution results showed that the Cur-PLGA-DPPs mainly accumulated in the lungs and liver after intravenous injection. Treatment with Cur-PLGA-DPPs effectively suppressed the infiltration of inflammatory cells in bronchoalveolar lavage fluid, and reduced bronchial wall thickening and goblet-cell hyperplasia compared to those in the phosphate-buffered-saline-treated control group. No significant changes in hematology and blood biochemistry parameters were observed after treatment with Cur-PLGA-DPPs. At equal curcumin concentrations, treatment with Cur-PLGA-DPPs exhibited better therapeutic efficacy than treatment with free curcumin. Our results suggest that the microscale Cur-PLGA-DPPs can be potentially used as a lung-targeted asthma therapy.