Changing clinical characteristics of pediatric inpatients with pneumonia during COVID-19 pandamic: a retrospective study.

BACKGROUND: The COVID-19 pandemic have impacts on the prevalence of other pathogens and people's social lifestyle. This study aimed to compare the pathogen, allergen and micronutrient characteristics of pediatric inpatients with pneumonia prior to and during the COVID-19 pandemic in a large tertiary hospital in Shanghai, China. METHODS: Patients with pneumonia admitted to the Department of Pediatric Pulmonology of Xinhua Hospital between March-August 2019 and March-August 2020 were recruited. And clinical characteristics of the patients in 2019 were compared with those in 2020. RESULTS: Hospitalizations for pneumonia decreased by 74% after the COVID-19 pandemic. For pathogens, virus, mycoplasma pneumoniae (MP) and mixed infection rates were all much lower in 2020 than those in 2019 (P < 0.01). Regarding allergens, compared with 2019, the positive rates of house dust mite, shrimp and crab were significantly higher in 2020 (P < 0.01). And for micronutrients, the levels of vitamin B2, B6, C and 25-hydroxyvitamin D (25(OH)D) in 2020 were observed to be significantly lower than those in 2019 (P < 0.05). For all the study participants, longer hospital stay (OR = 1.521, P = 0.000), milk allergy (OR = 6.552, P = 0.033) and calcium (Ca) insufficiency (OR = 12.048, P = 0.019) were identified as high-risk factors for severe pneumonia by multivariate analysis. CONCLUSIONS: The number of children hospitalized with pneumonia and incidence of common pathogen infections were both reduced, and that allergy and micronutrient status in children were also changed after the outbreak of the COVID-19 pandemic.

M1 polarization of macrophages promotes stress-induced hair loss via interleukin-18 and interleukin-1ß.

Stress-induced hair loss is a prevalent health concern, with mechanisms that remain unclear, and effective treatment options are not yet available. In this study, we investigated whether stress-induced hair loss was related to an imbalanced immune microenvironment. Screening the skin-infiltrated immune cells in a stressed mouse model, we discovered a significant increase in macrophages upon stress induction. Clearance of macrophages rescues mice from stress-induced hair shedding and depletion of hair follicle stem cells (HFSCs) in the skin, demonstrating the role of macrophages in triggering hair loss in response to stress. Further flow cytometry analysis revealed a significant increase in M1 phenotype macrophages in mice under stressed conditions. In searching for humoral factors mediating stress-induced macrophage polarization, we found that the hormone Norepinephrine (NE) was elevated in the blood of stressed mice. In addition, in-vivo and in-vitro studies confirm that NE can induce macrophage polarization toward M1 through the ß-adrenergic receptor, Adrb2. Transcriptome, enzyme-linked immunosorbent assay (ELISA), and western blot analyses reveal that the NLRP3/caspase-1 inflammasome signaling and its downstream effector interleukin 18 (IL-18) and interleukin 1 beta (IL-1ß) were significantly upregulated in the NE-treated macrophages. However, inhibition of the NE receptor Adrb2 with ICI118551 reversed the upregulation of NLRP3/caspase-1, IL-18, and IL-1ß. Indeed, IL-18 and IL-1ß treatments lead to apoptosis of HFSCs. More importantly, blocking IL-18 and IL-1ß signals reversed HFSCs depletion in skin organoid models and attenuated stress-induced hair shedding in mice. Taken together, this study demonstrates the role of the neural (stress)-endocrine (NE)-immune (M1 macrophages) axis in stress-induced hair shedding and suggestes that IL-18 or IL-1ß may be promising therapeutic targets.

The analysis of risk factors for recurrent wheezing in infants and clinical intervention.

Background: Asthma is one of the most common chronic diseases affecting children's health, and recurrent wheezing in infants is closely related to childhood asthma. However, up to now, there is a lack of unified diagnostic criteria and interventions for recurrent wheezing in infants. By analyzing and discussing the risk factors of recurrent wheezing in infants and related intervention measures, we aim to take individualized treatment for different children and reduce the occurrence of recurrent wheezing in infants. Methods: From January 2017 to December 2020, children under 3 years old who were admitted to the Department of Pediatric Respiratory of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine with the chief complaint of wheezing for the first time and were clinically diagnosed with bronchiolitis, asthmatic bronchopneumonia and asthmatic bronchitis were retrospectively analyzed through telephone questionnaires. These children were divided into two groups based on whether the wheezing occurred again after discharge. The demographic characteristics, clinical treatment, imaging characteristics, and related interventions and outcomes after discharge were analyzed in both groups. Results: Among the 523 children under 3 years old who were hospitalized due to wheezing, 264 (50.5%) did not have wheezing after discharge, and 259 (49.5%) still had wheezing after discharge. Both chi-squared test and multivariate analysis showed that male, history of eczema, history of rhinitis, history of wheezing before hospitalization, family smoke exposure, mycoplasma infection and inhalation allergen sensitization were risk factors for recurrent wheezing in infants and young children (P<0.05). Simultaneously, Cox survival curve showed that different intervention time and intervention methods would lead to different prognosis. Conclusions: (I) Male, with a history of eczema, rhinitis, wheezing before hospitalization, family environment smoke exposure, mycoplasma infection and a history of inhalation allergy are high risk factors for recurrent wheezing in the recurrent wheezing group, and are more likely to have recurrent wheezing after discharge, with shorter days of wheezing control; (II) there was a significant interaction between mycoplasma infection and a history of inhalation allergy in infants with the risk of recurrent wheezing; (III) long-term intervention for children with wheezing for 4 weeks or more after discharge can reduce the probability of recurrent wheezing; (IV) for children of male, with a history of eczema or rhinitis, the most effective intervention to reduce the probability of recurrent wheezing is long-term inhaled corticosteroids (ICS) treatment after discharge.

Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.

Exposure of mitochondrial DNA (mtDNA) to the cytosol activates innate immune responses. But the mechanisms by which mtDNA crosses the inner mitochondrial membrane are unknown. Here, we found that the inner mitochondrial membrane protein prohibitin 1 (PHB1) plays a critical role in mtDNA release by regulating permeability across the mitochondrial inner membrane. Loss of PHB1 results in alterations in mitochondrial integrity and function. PHB1-deficient macrophages, serum from myeloid-specific PHB1 KO (Phb1MyeKO) mice, and peripheral blood mononuclear cells from neonatal sepsis patients show increased interleukin-1ß (IL-1ß) levels. PHB1 KO mice are also intolerant of lipopolysaccharide shock. Phb1-depleted macrophages show increased cytoplasmic release of mtDNA and inflammatory responses. This process is suppressed by cyclosporine A and VBIT-4, which inhibit the mitochondrial permeability transition pore (mPTP) and VDAC oligomerization. Inflammatory stresses downregulate PHB1 expression levels in macrophages. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to PHB1 to inhibit mPTP opening. Downregulation of PHB1 results in enhanced interaction between AFG3L2 and SPG7, mPTP opening, mtDNA release, and downstream inflammatory responses.

Effect of Bufalin-PLGA Microspheres in the Alleviation of Neuropathic Pain via the CCI Model.

The treatment of neuropathic pain (NPP) is considered challenging, while the search for alternative medication is striving. NPP pathology is related with the expression of both the purinergic 2X7 (P2X7) receptor and the transient receptor potential vanilloid 1 receptor (TRPV1). Bufalin is a traditional Chinese medication derived from toad venom with pronounced antitumor, analgesic, and anti-inflammatory properties. However, poor solubility, rapid metabolism, and the knowledge gap on its pain alleviation mechanism have limited the clinical application of bufalin. Hence, the purpose of this study is to illustrate the NPP alleviation mechanism of bufalin via chronic constriction injury (CCI). To address the concern on fast metabolism, bufalin-PLGA microspheres (MS) were prepared via membrane emulsification to achieve prolonged pain-relieving effects. Western blot, real-time PCR, immunofluorescence, and molecular docking were employed to demonstrate the therapeutic action of bufalin on NPP. The results showed enhanced thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) after the administration of both bufalin and bufalin-PLGA MS in the CCI rats. Prolonged pain-relieving effects for up to 3 days with reduced dose frequency was achieved via bufalin-PLGA MS. In the CCI rats treated with bufalin-PLGA MS, the expression levels of protein and mRNA in TRPV1 and P2X7, both localized in the dorsal root ganglion (DRG), were reduced. Moreover, bufalin-PLGA MS effectively reduced the levels of IL-1ß, IL-18, IL-6, and TNF-α in the CCI group. The results from molecular docking suggested a possible mechanism of NPP alleviation of bufalin through binding to P2X7 receptors directly. The administration of bufalin-PLGA MS prepared by membrane emulsification demonstrated promising applications for sustained effect on the alleviation of NPP.

Immune Regulation of Heme Oxygenase-1 in Allergic Airway Inflammation.

Heme oxygenase-1 (HO-1) is not only a rate-limiting enzyme in heme metabolism but is also regarded as a protective protein with an immunoregulation role in asthmatic airway inflammation. HO-1 exerts an anti-inflammation role in different stages of airway inflammation via regulating various immune cells, such as dendritic cells, mast cells, basophils, T cells, and macrophages. In addition, the immunoregulation role of HO-1 may differ according to subcellular locations.

Traditional Chinese Medicine Extract Properties Incorporated Energy Analysis for Membrane Concentration Processes.

This work focuses on the energy analysis of the membrane concentration systems that process traditional Chinese medicine extracts with dynamic properties incorporated, particularly for reverse osmosis (RO) and membrane distillation (MD) processes. The evaluation of process energy consumption was achieved by integrating the empirical properties correlations of Brix and other characteristics properties of the feed (e.g., density and heat capacity). The dynamic SEC analysis for RO process was largely dependent on the feed pressure, reported at 50 kWh/m3 at feed pressure of 0.9 MPa with less than 50% water removal. The occurrence of foaming at above 50% water removal caused discrepancies between the simulated flux results and the experimentally acquired results in RO, whereas the estimated dynamic SEC for MD process did not show a strong correlation with the temperatures selected in this study, ranging from 900 to 1000 kWh/m3. This approach can be adapted into the design and zoptimization for the concentration process of other herbal extracts by membrane technologies, allowing comprehensive understanding into the energy analysis in future study.

Gene-gene and gene-environment interactions on cord blood total IgE in Chinese Han children.

BACKGROUND: IL13, IL4, IL4RA, FCER1B and ADRB2 are susceptible genes of asthma and atopy. Our previous study has found gene-gene interactions on asthma between these genes in Chinese Han children. Whether the interactions begin in fetal stage, and whether these genes interact with prenatal environment to enhance cord blood IgE (CBIgE) levels and then cause subsequent allergic diseases have yet to be determined. This study aimed to determine whether there are gene-gene and gene-environment interactions on CBIgE elevation among the aforementioned five genes and prenatal environmental factors in Chinese Han population. METHODS: 989 cord blood samples from a Chinese birth cohort were genotyped for nine single-nucleotide polymorphisms (SNPs) in the five genes, and measured for CBIgE levels. Prenatal environmental factors were collected using a questionnaire. Gene-gene and gene-environment interactions were analyzed with generalized multifactor dimensionality methods. RESULTS: A four-way gene-gene interaction model (IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713) was regarded as the optimal one for CBIgE elevation (testing balanced accuracy = 0.5805, P = 9.03 × 10-4). Among the four SNPs, only IL13 rs20541 was identified to have an independent effect on elevated CBIgE (odds ratio (OR) = 1.36, P = 3.57 × 10-3), while the other three had small but synergistic effects. Carriers of IL13 rs20541 TT, IL13 rs1800925 CT/TT, IL4 rs2243250 TT and ADRB2 rs1042713 AA were estimated to be at more than fourfold higher risk for CBIgE elevation (OR = 4.14, P = 2.69 × 10-2). Gene-environment interaction on elevated CBIgE was found between IL4 rs2243250 and maternal atopy (OR = 1.41, P = 2.65 × 10-2). CONCLUSIONS: Gene-gene interaction between IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713, and gene-environment interaction between IL4 rs2243250 and maternal atopy begin in prenatal stage to augment IgE production in Chinese Han children.

A pilot study to evaluate the role of circulation CD4+ CCR6+ CRTh2+ cell in predicting risk of asthma in wheezing children.

BACKGROUND: Wheezing is common in younger children and often related to viral infection. It is lack of reliable indicators for asthma prediction. OBJECTIVE: To evaluate the relationship between circulation CD4+CCR6+CRTh2+ memory Th2 cells and asthma diagnosis in wheezing children. METHODS: A prospective study was performed in children under 5 years old presented with wheezing or at last one episode of documented wheezing history. After inclusion, the level of serum allergen-specific serum IgE (sIgE) and circulating CD4+CCR6+CRTh2+cells were detected. The patients' personal and family histories of allergic disease were acquired by questionnaire. The children were followed up over 2 years. Diagnosis of asthma was assessed at the end follow-up. The risk factors in predicting asthma diagnosis were evaluated. RESULTS: A total of 43 children completed follow-up. Higher wheezing frequency were found in children with asthma diagnosis. The mean of circulating CD4+CCR6+CRTh2+cells in children diagnosed with or without asthma was 1.6 %±0.8 and 0.8 %±0.6 %, respectively, and was significantly higher in children diagnosed with asthma (p < 0.01). There was no significant difference between children with and without allergic diseases history or family allergic diseases in level of circulating CD4+CCR6+CRTh2+ cells. Logistic regression analysis indicated that circulating CD4+CCR6+CRTh2+ cells (EXP, 8.986; 95 % CI,1.886-42.816) and wheezing frequency(EXP, 0.127; 95 % CI, 0.023-0.703)were high risk factors for asthma. CONCLUSIONS: Our exploratory study shown that circulating CD4+CCR6+CRTh2+ memory Th2 cells increased in asthma diagnosed children and it was a high-risk factor for asthma. Detection of this type of cells could be helpful in predicting the risk of asthma in wheezing children.

Utility of basophil activation test for predicting the outcome of wheezing in children: a pilot study.

BACKGROUND: No reliable biological marker for the diagnosis of asthma in younger children is currently available. In this study, we analyzed the differences in basophil activation test (BAT) results among children with recurrent wheezing episodes who had different asthma outcomes. RESULTS: A prospective cohort study was conducted in children aged under 5 years who visited our pediatric respiratory clinic and ward for wheezing. After enrollment, the participants provided samples for a CD63-based BAT performed using an inhalant allergen mixture as a stimulant. Histories of personal allergic diseases and family allergic diseases were evaluated by using a questionnaire. All participants were followed up for 2 years, and their asthma outcomes were evaluated at the end of the follow-up period. The correlation between the BAT results and asthma outcomes was analyzed. Of the 45 originally enrolled children, 38 completed both the follow-up and a BAT. After stimulation with the inhalant mixture, the CD63 expression on basophils and the rate of positive CD63-based BAT results in children diagnosed with asthma were both significantly higher than those in children who were not diagnosed with asthma (p < 0.05 and p < 0.01, respectively). For the prediction of asthma, the positive predictive value and negative predictive value of CD63-based BAT was 71.8 and 69.2%, respectively. The positive likelihood ratio and negative likelihood ratio of CD63-based BAT were 1.70 and 0.3, respectively. CONCLUSIONS: Our pilot study indicates that CD63-based BAT has potential clinical value for predicting asthma outcome in young children with wheezing episodes.

Mammalian Target of Rapamycin Signaling Enhances Ovalbumin-Induced Neutrophilic Airway Inflammation by Promoting Th17 Cell Polarization in Murine Noneosinophilic Asthma Model.

Background: T helper 17 (Th17) is regarded as key immune cell in the pathogenesis of noneosinophilic asthma (NEA) due to the recruitment of neutrophils into the airways. The mammalian target of rapamycin (mTOR) is an important signaling molecule that plays a critical role in immune regulation. This study focused on mTOR signaling pathway in the regulation of Th17-mediated neutrophilic airway inflammation. Methods: Ovalbumin (OVA) T cell receptor transgenic DO11.10 mice (DO11.10 mice) were used to establish NEA model, and few mice received specific mTORC1 inhibitor rapamycin (RAPA) before intranasal administration of OVA. The severity of airway inflammation was determined by differential cell counts in bronchoalveolar lavage (BAL) fluids and histopathologic lung analysis. The levels of various cytokines in BAL fluids and lung tissues were measured. To determine the role of mTORC1 signaling in Th17 differentiation, naive T cells from wild-type (WT) and TSC1 knockout (KO) mice were cultured in Th17 skewing condition with or without RAPA in vitro and the production of IL-17A was compared. Results: Treatment with RAPA markedly attenuated OVA-induced neutrophilic airway inflammation in DO11.10 mice. Also the production of IL-17A was inhibited without affecting the production of interferon-γ (IFN-γ) and IL-4 in lungs. Furthermore, RAPA suppressed differentiation of Th17 cells in vitro, whereas enhanced activity of mTORC1 promoted Th17 cell differentiation and increased the expression of Th17-related transcription factors RORγt and RORα. Conclusion: These results suggested that mTOR promoted Th17 cell polarization and enhanced OVA-induced neutrophilic airway inflammation in experimental NEA.

Primary immunodeficiency disease: a retrospective study of 112 Chinese children in a single tertiary care center.

BACKGROUND: Primary immunodeficiency disease (PID) is a disorder caused by an inherited flaw in the immune system that increases the susceptibility to infections. METHODS: In this study, 112 children with PID were diagnosed and classified based on the 2017 criteria presented by the International Union of Immunological Societies (IUIC) in a single tertiary care center from January 2013 to November 2018. We retrospectively studied the clinical features of those PID children and followed-up them as well. RESULTS: It was revealed that male/female ratio was 6:1. The most frequent diagnosed PID was severe combined immunodeficiency (SCID) (28.6%) and hyper-IgM (HIGM) syndrome (24.1%), followed by predominantly antibody deficiencies (17.8%). Combined immunodeficiencies with associated or syndromic features (12.5%) and congenital defects of phagocyte number, function, or both (10.7%) were less common in our center compared with SCID and HIGM syndrome. Besides, we found that 20 children (17.8%) had a positive family history of PID, and almost all cases (97.3%) had a history of recurrent infection. Recurrent respiratory tract infection was among the most common symptoms, followed by the bacterial infection of the skin and mucous membranes and diarrhea. Additionally, adverse event following immunization (AEFI) was found in 20.5% of the patients, and immune disorder was commonly observed in PID patients. In the present study, 47 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), and 2-year overall survival (OS) rate for these patients was 78.7% (37/47). It is noteworthy that OS widely differed among PID patients with different phenotypes who underwent allo-HSCT. The 2-year OS rate for SCID, HIGM syndrome, and the remaining of PID patients who underwent allo-HSCT was 14.3, 83.3, and 100%, respectively. CONCLUSIONS: PID typically emerges at early age. Recurrent infection and serious infection were the most common clinical manifestations. Allo-HSCT is a relatively effective therapeutic strategy for PID patients.

Reliability and validity of the Chinese version of the Test for Respiratory and Asthma Control in Kids (TRACK) in preschool children with asthma: a prospective validation study.

OBJECTIVE: The limited existing asthma control questionnaires that are available for children 5 years of age or younger in China mostly assess only the impairment domain of asthma control. Here, the English version of the Test for Respiratory and Asthma Control in Kids (TRACK) was translated into Chinese and validated for its application in asthma control in preschool children. DESIGN: Prospective validation study. SETTING AND PARTICIPANTS: A total of 321 Chinese preschool children suffering from asthma completed the study from December 2017 to February 2018. METHOD: The TRACK translation into Chinese employed the translation and back translation technique. The caregivers of the preschool children with asthma symptoms completed TRACK during two clinical visits over 4-6 weeks. Moreover, the physicians completed a Global Initiative for Asthma (GINA)-based asthma control survey at both visits. The utility of TRACK for assessing the change in asthma control status and its reliability and discriminant validity were evaluated. RESULTS: The Chinese version of TRACK showed internal consistency reliability values of 0.63 and 0.71 at each visit, respectively (Cronbach's α). The test-retest reliability was 0.62 for individuals whose GINA-based assessment results were the same at both visits (n=206). The TRACK scores for the children in the various asthma control categories were significantly different (p<0.001). Children recommended for increased treatment by the physicians had lower TRACK scores than those recommended for no change in treatment or decreased treatment (p<0.001). CONCLUSION: The study verifies the validity and reliability of the Chinese version of TRACK. Changes in the TRACK scores effectively reflected the level of asthma control in preschool children and guided further treatment strategies. TRIAL REGISTRATION NUMBER: NCT02649803.

Pilot study of expanded carrier screening for 11 recessive diseases in China: results from 10,476 ethnically diverse couples.

Expanded carrier screening (ECS) has been demonstrated to increase the detection rate of carriers compared with traditional tests. The aim of this study was to assess the potential value of ECS for clinical application in Southern China, a region with high prevalence of thalassemia and with diverse ethnic groups, and to provide a reference for future implementations in areas with similar population characteristics. A total of 10,476 prenatal/preconception couples from 34 self-reported ethnic groups were simultaneously tested and analyzed anonymously for 11 Mendelian disorders using targeted next-generation sequencing. Overall, 27.49% of individuals without self-reported family history of disorders were found to be carriers of at least 1 of the 11 conditions, and the carrier frequency varied greatly between ethnic groups, ranging from 4.15% to 81.35%. Furthermore, 255 couples (2.43%) were identified as carrier couples at an elevated risk having an affected baby, sixty-five of which would not have been identified through the existing screening strategy, which only detects thalassemia. The modeled risk of fetuses being affected by any of the selected disorders was 531 per 100,000 (95% CI, 497-567 per 100,000). Our data demonstrate the feasibility of ECS, and provide evidence that ECS is a promising alternative to traditional one-condition screening strategies. The lessons learned from this experience should be applicable for other countries or regions with diverse ethnic groups.

Association of asthma diagnosis with leptin and adiponectin: a systematic review and meta-analysis.

There is some evidence which shows that higher levels of serum leptin and lower levels of serum adiponectin are associated with the diagnosis of asthma. This meta-analysis evaluated the association of serum leptin and adiponectin levels with the diagnosis of asthma. We searched the MEDLINE, Cochrane, EMBASE and CINAHL Plus databases up to July 2015. Eligible studies were randomized controlled trials, prospective studies, retrospective studies, case-control studies and cohort studies. 13 studies with 3642 patients were included in the study. The meta-analysis found that in the overall study population, the diagnosis of asthma was associated with higher levels of leptin (pooled standardized difference in means=0.867, 95% CI 0.416 to 1.318, p<0.001) and lower levels of adiponectin (pooled standardized difference in means=-0.371, 95% CI -0.728 to -0.014, p=0.042) in patients with asthma compared with controls. Subgroup analysis found that higher leptin levels were associated with asthma both in adults (standardized difference in means=1.374, 95% CI 0.621 to 2.126, p<0.001) and children (standardized difference in means=0.302, 95% CI 0.010 to 0.594, p=0.042). However, borderline association of adiponectin with asthma was seen in adults (p=0.05), but not in children (p=0.509). Sensitivity analysis indicated that the findings for leptin were robust. Our findings are consistent with higher levels of serum leptin being associated with asthma regardless of age, and low adiponectin levels being associated with asthma in adults only.

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

The 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 antigen-induced 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.

Basophil-associated OX40 ligand participates in the initiation of Th2 responses during airway inflammation.

Asthma is characterized by increased airway submucosal infiltration of T helper (Th) cells and myeloid cells that co-conspire to sustain a chronic inflammation. While recent studies have demonstrated that the myeloid basophils promote Th2 cells in response to various types of allergens, the underlying mechanisms are poorly understood. Here, we found for the first time that in a mouse model of allergic asthma basophils highly expressed OX40 ligand (OX40L) after activation. Interestingly, blockade of OX40-OX40L interaction suppressed basophils-primed Th2 cell differentiation in vitro and ameliorated ovalbumin (OVA)-induced allergic eosinophilic inflammation mediated by Th2 activation. In accordance, the adoptive transfer of basophils derived from mediastinal lymph nodes (MLN) of OVA-immunized mice triggered a robust Th2 response and eosinophilic inflammation in wild-type mice but largely muted in OX40(-/-) mice and mice receiving OX40L-blocked basophils. Taken together, our results reveal a critical role of OX40L presented by the activated basophils to initiate Th2 responses in an allergic asthma model, implicating OX40-OX40L signaling as a potential therapeutic target in the treatment of allergic airway inflammation.

Heme oxygenase-1 ameliorates dextran sulfate sodium-induced acute murine colitis by regulating Th17/Treg cell balance.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a group of autoimmune diseases characterized by nonspecific inflammation in the gastrointestinal tract. Recent investigations suggest that activation of Th17 cells and/or deficiency of regulatory T cells (Treg) is involved in the pathogenesis of IBD. Heme oxygenase (HO)-1 is a protein with a wide range of anti-inflammatory and immune regulatory function, which exerts significantly protective roles in various T cell-mediated diseases. In this study, we aim to explore the immunological regulation of HO-1 in the dextran sulfate sodium-induced model of experimental murine colitis. BALB/c mice were administered 4% dextran sulfate sodium orally; some mice were intraperitoneally pretreated with HO-1 inducer hemin or HO-1 inhibitor stannum protoporphyrin IX. The results show that hemin enhances the colonic expression of HO-1 and significantly ameliorates the symptoms of colitis with improved histological changes, accompanied by a decreased proportion of Th17 cells and increased number of Tregs in mesenteric lymph node and spleen. Moreover, induction of HO-1 down-regulates retinoic acid-related orphan receptor γt expression and IL-17A levels, while promoting Treg-related forkhead box p3 (Foxp3) expression and IL-10 levels in colon. Further study in vitro revealed that up-regulated HO-1 switched the naive T cells to Tregs when cultured under a Th17-inducing environment, which involved in IL-6R blockade. Therefore, HO-1 may exhibit anti-inflammatory activity in the murine model of acute experimental colitis via regulating the balance between Th17 and Treg cells, thus providing a possible novel therapeutic target in IBD.

Basophils as a primary inducer of the T helper type 2 immunity in ovalbumin-induced allergic airway inflammation.

Antigen-induced allergic airway inflammation is mediated by T helper type 2 (Th2) cells and their cytokines, but the mechanism that initiates the Th2 immunity is not fully understood. Recent studies show that basophils play important roles in initiating Th2 immunity in some inflammatory models. Here we explored the role of basophils in ovalbumin (OVA) -induced airway allergic inflammation in BALB/c mice. We found that OVA sensitization and challenge resulted in a significant increase in the amount of basophils in blood and lung, along with the up-regulation of activation marker of CD200R. However, depletion of basophils with MAR-1 or Ba103 antibody attenuated airway inflammation, represented by the significantly decreased amount of the Th2 subset in spleen and draining lymph nodes, interlukin-4 level in lung and OVA-special immunoglobulin E (sIgE) levels in serum. On the other hand, adoptive transfer of basophils from OVA-challenged lung tissue to naive BALB/c mice provoked the Th2 immune response. In addition, pulmonary basophils from OVA-challenged mice were able to uptake DQ-OVA and express MHC class II molecules and CD40 in vivo, as well as to release interleukin-4 following stimulation by IgE-antigen complexes and promote Th2 polarization in vitro. These findings demonstrate that basophils may participate in Th2 immune responses in antigen-induced allergic airway inflammation and that they do so through facilitating antigen presentation and providing interleukin-4.