Hemin-primed dendritic cells suppress allergic airway inflammation through releasing extracellular vesicles

Abstract

Hemin, a substrate of heme oxygenase (HO)-1, induces HO-1 expression on a variety of cells to exert anti-oxidant and anti-inflammatory roles. However, the role of HO-1 in allergic diseases for dendritic cells (DCs) is not fully understood. Here, we report that HO-1 modulates asthmatic airway inflammation by hemin-treated DC-released extracellular vesicles (DCEVs). Following induction of bone marrow-derived DCs by hemin and then by house dust mite (HDM) in vitro, mouse CD4+ naïve T cells were cocultured with DCEVs to determine T helper (h) cell differentiation. C57BL/6 mice were sensitized by different stimuli-induced DCEVs and challenged with HDM to analyze the changes of inflammatory cells and cytokines in the lung and bronchoalveolar lavage fluid. The results showed that hemin-treated DCEVs (hemin-DCEVs) express phosphatidylserine (PS), CD81, heat shock protein 70, and HO-1, which facilitates regulatory T (Treg) cells differentiation in vitro and in vivo. In HDM-induced asthmatic mouse model, hemin-DCEVs inhalation reduced eosinophils infiltration and mucus secretion in the airway, decreased the levels of IL-4, IL-5, and IL-13 in the lung and the number of Th2 cells in mediastinal lymph nodes (MLNs), and increased the number of Treg cells in MLNs. Thus, our study demonstrated, for the first time, that EVs from HO-1overexpressing DCs alleviate allergic airway inflammation of eosinophilic asthma by potentiating Treg cells differentiation and limiting proinflammatory cytokine secretion, which expands our understanding of HO-1 function, opening the door for HO-1 inducer-like hemin as a novel therapeutic strategy for asthma or other allergic diseases.

Crosstalk between ILC2s and Th2 CD4+ T Cells in Lung Disease

“…Anti-F4/80 treatment of OVA-induced asthmatic mice inhibited alternately activated macrophages and also attenuated Th2 cell response in lung tissue [ 70 ]. Similarly, reducing the levels of IL-4, IL-5, and IL-13 in the lung and the number of Th2 cells in mediastinal lymph nodes, while increasing the number of Treg cells in mediastinal lymph nodes, can alleviate allergic airway inflammation [ 71 ]. Acupuncture also seems to reduce airway inflammation and airway hyperreactivity (AHR) in asthmatic patients by correcting the imbalance of CD4 + T lymphocyte subsets (Th1/Th2 and Treg/Th17) [ 72 ].…”

Recent advances in extracellular vesicle engineering and its applications to regenerative medicine

“…Based on these effects, when Hem treated DC-derived treated EVs (Hem-EV) were administered via inhalation to a house dust mite (HDM) induced asthmatic mouse model, it reduced eosinophil infiltration and mucus secretion in the airways, decreased the levels of IL-4, IL-5, and IL-13 in the lungs, and reduced the Th2 cells number in the mediastinal lymph nodes (MLNs), while increasing the number of regulatory T (Treg) cells in the MLNs. These immune-regulatory effects are believed to be attributed to the regulation of HO-1 expression in Hem-EVs [ 81 ]. The resveratrol (Res), a well-known antioxidant compound and non-flavonoid polyphenol, was successfully loaded into EV derived from primary microglia.…”

“… Target cell Treatment material Concentration Ref. 1 RAW 264.7 Gemfibrozil 100 μg/ml [ 77 ] 2 RAW 264.7 Silibinin 50 μg/ml [ 78 ] 3 RAW 264.7 Edaravone 87.5 μg/ml [ 79 ] 4 SMC Cystatin C 1.95 μg/ml [ 80 ] 5 Dendritic cell Hemin 4.89 μg/ml [ 81 ] 6 Primary microglia and neurons Resveratrol 9.13 μg/ml [ 17 ] 7 BMSC TGFβ3 50 ng/ml [ 15 ] 8 BMSC Erythropoietin (EPO) 0.84 μg/ml [ 82 ] 9 BMSC tauroursodeoxycholic acid (TUDCA) 1.3 mg/ml [ 95 ] 10 BMSC Dimethyloxaloylglycine (DMOG) 0.17 mg/ml [ 96 ] 11 UCMSC Tanshinone IIA 2.94 μg/ml [ 85 ] 12 UCMSC Melatonin 4.65 μg/ml [ 16 ] 13 ADMSC Melatonin 4.65 μg/ml [ 87 ] ...…”

Tolerogenic dendritic cells in radiation-induced lung injury

“…Notably, it has been reported that many conventional DCs(cDCs) are located in the mucous membranes of the airway ducts ( 107 – 109 ). These cells extend pseudopods between epithelial cells to capture antigens present within the airway cavity ( 102 , 110 , 111 ). Based on their functional differences, cDCs are further categorized into two subsets: cDC1 and cDC2.…”