Heme oxygenase‐1 inhibits basophil maturation and activation but promotes its apoptosis in T helper type 2‐mediated allergic airway inflammation

Abstract

SummaryThe anti-inflammatory role of heme oxygenase-1 (HO-1) has been studied extensively in many disease models including asthma. Many cell types are anti-inflammatory targets of HO-1, such as dendritic cells and regulatory T cells. In contrast to previous reports that HO-1 had limited effects on basophils, which participate in T helper type 2 immune responses and antigeninduced allergic airway inflammation, we demonstrated in this study, for the first time, that the up-regulation of HO-1 significantly suppressed the maturation of mouse basophils, decreased the expression of CD40, CD80, MHC-II and activation marker CD200R on basophils, blocked DQ-ovalbumin uptake and promoted basophil apoptosis both in vitro and in vivo, leading to the inhibition of T helper type 2 polarization. These effects of HO-1 were mimicked by exogenous carbon monoxide, which is one of the catalytic products of HO-1. Furthermore, adoptive transfer of HO-1-modified basophils reduced ovalbumin-induced allergic airway inflammation. The above effects of HO-1 can be reversed by the HO-1 inhibitor Sn-protoporphyrin IX. Moreover, conditional depletion of basophils accompanying hemin treatment further attenuated airway inflammation compared with the hemin group, indicating that the protective role of HO-1 may involve multiple immune cells. Collectively, our findings demonstrated that HO-1 exerted its anti-inflammatory function through suppression of basophil maturation and activation, but promotion of basophil apoptosis, providing a possible novel therapeutic target in allergic asthma.

Airway epithelial TSLP production of TLR2 drives type 2 immunity in allergic airway inflammation

“…Consistently, we found that increased expression of co‐stimulatory molecules on lung basophils and DCs was dramatically reversed by TSLP antibody or TLR2 deficiency, which was rescued by intranasal administration of recombinant TSLP. This maturation behavior closely coincides with their role in the induction of type 2 responses, as we and others have previously reported . Blockade of airway TSLP decreased IL‐4 production in lung basophils, suggesting its critical role in the induction of Th2 response through triggering initial IL‐4 synthesis.…”

“…Blood samples were collected for DC and basophil counts. A single cell suspension was obtained as we previously described . For some experiments, lung single cell suspensions were stimulated with 100 ng/mL recombinant mouse TSLP or anti‐TSLP antibody for 24 h and were subjected to flow cytometric analysis.…”

“…For analysis of apoptosis, lung cells were stained with antibodies listed above and Annexin V FITC and 7‐AAD (BD Pharmingen, San Diego, California, USA). Intracellular IL‐4 staining was performed as previously reported . Briefly, cells were stimulated by 20 ng/mL PMA (Sigma–Aldrich) and 1 μg/mL ionomycin (Sigma–Aldrich) for further 6 h and were stimulated with Brefeldin A (eBioscience) at the ratio of 1:1000 for further 2 h. The collected cells were surface stained with CD4 FITC and IL‐4 PE (BD Pharmingen).…”

Inhibition of lipopolysaccharide-induced inflammation via the protective role of T regulatory cells in the fetal liver in a late-pregnancy preterm mouse model

“…Tissue repair is enhanced by HO-1 ( 24 ), a major enzyme for prevention of inflammation. During late gestational inflammation, dysregulation in maternal immune response occurs and is mediated by HO-1 ( 25 ).…”

Heme Catabolic Pathway in Inflammation and Immune Disorders

“…It has been shown that HO-1 induction by a retroviral vector could suppress TNF-induced cell death (Kushida et al, 2002). In ovalbumin-induced allergic asthma mice, HO-1 inhibits basophil maturation and activation and promotes basophil apoptosis (Zhong et al, 2016). These results show that HO-1 has an anti-inflammatory effect.…”