Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia.

Zinc (Zn) is required for proper immune function and host defense. Zn homeostasis is tightly regulated by Zn transporters that coordinate biological processes through Zn mobilization. Zn deficiency is associated with increased susceptibility to bacterial infections, including Streptococcus pneumoniae, the most commonly identified cause of community-acquired pneumonia. Myeloid cells, including macrophages and dendritic cells (DCs), are at the front line of host defense against invading bacterial pathogens in the lung and play a critical role early on in shaping the immune response. Expression of the Zn transporter ZIP8 is rapidly induced following bacterial infection and regulates myeloid cell function in a Zn-dependent manner. To what extent ZIP8 is instrumental in myeloid cell function requires further study. Using a novel, myeloid-specific, Zip8 knockout model, we identified vital roles of ZIP8 in macrophage and DC function upon pneumococcal infection. Administration of S. pneumoniae into the lung resulted in increased inflammation, morbidity, and mortality in Zip8 knockout mice compared with wild-type counterparts. This was associated with increased numbers of myeloid cells, cytokine production, and cell death. In vitro analysis of macrophage and DC function revealed deficits in phagocytosis and increased cytokine production upon bacterial stimulation that was, in part, due to increased NF-κB signaling. Strikingly, alteration of myeloid cell function resulted in an imbalance of Th17/Th2 responses, which is potentially detrimental to host defense. These results (for the first time, to our knowledge) reveal a vital ZIP8- and Zn-mediated axis that alters the lung myeloid cell landscape and the host response against pneumococcus.

ZIP8-Mediated Intestinal Dysbiosis Impairs Pulmonary Host Defense against Bacterial Pneumonia.

Pneumococcal pneumonia is a leading cause of morbidity and mortality worldwide. An increased susceptibility is due, in part, to compromised immune function. Zinc is required for proper immune function, and an insufficient dietary intake increases the risk of pneumonia. Our group was the first to reveal that the Zn transporter, ZIP8, is required for host defense. Furthermore, the gut microbiota that is essential for lung immunity is adversely impacted by a commonly occurring defective ZIP8 allele in humans. Taken together, we hypothesized that loss of the ZIP8 function would lead to intestinal dysbiosis and impaired host defense against pneumonia. To test this, we utilized a novel myeloid-specific Zip8KO mouse model in our studies. The comparison of the cecal microbial composition of wild-type and Zip8KO mice revealed significant differences in microbial community structure. Most strikingly, upon a S. pneumoniae lung infection, mice recolonized with Zip8KO-derived microbiota exhibited an increase in weight loss, bacterial dissemination, and lung inflammation compared to mice recolonized with WT microbiota. For the first time, we reveal the critical role of myeloid-specific ZIP8 on the maintenance of the gut microbiome structure, and that loss of ZIP8 leads to intestinal dysbiosis and impaired host defense in the lung. Given the high incidence of dietary Zn deficiency and the ZIP8 variant allele in the human population, additional investigation is warranted to improve surveillance and treatment strategies.

Increased TREM-2 expression on the subsets of CD11c+ cells in the lungs and lymph nodes during allergic airway inflammation.

Dendritic cells (DCs) are professional APCs that traffic to the draining lymph nodes where they present processed antigens to naïve T-cells. The recently discovered triggering receptor expressed on myeloid cells (TREM)-2 has been shown to be expressed on DCs in several disease models, however, its role in asthma is yet to be elucidated. In the present study, we examined the effect of allergen exposure on TREM-2 expression in the airways and on DC subsets in the lung and lymph nodes in murine model of allergic airway inflammation. Sensitization and challenge with ovalbumin reproduced hallmark features of asthma. TREM-2 mRNA expression in the whole lung was significantly higher in the OVA-sensitized and -challenged mice which was associated with increased protein expression in the lungs. Analysis of CD11c+MHC-IIhi DCs in the lung and draining lymph nodes revealed that allergen exposure increased TREM-2 expression on all DC subsets with significantly higher expression in the lymph nodes. This was associated with increased mRNA expression of Th2 and Th17 cytokines. Further analyses showed that these TREM-2+ cells expressed high levels of CCR-7 and CD86 suggesting a potential role of TREM-2 in mediating maturation and migration of DC subsets in allergic airway inflammation.

Vitamin D and Bronchial Asthma: An Overview of Data From the Past 5 Years.

PURPOSE: Vitamin D is a potent immunomodulator capable of dampening inflammatory signals in several cell types involved in the asthmatic response. Its deficiency has been associated with increased inflammation, exacerbations, and overall poor outcomes in patients with asthma. Given the increase in the prevalence of asthma over the past few decades, there has been enormous interest in the use of vitamin D supplementation as a potential therapeutic option. Here, we critically reviewed the most recent findings from in vitro studies, animal models, and clinical trials regarding the role of vitamin D in treating bronchial asthma. METHODS: Using the key terms [Vitamin D, asthma, clinical trials, in vivo and in vitro studies], the [PubMed, Google Scholar] databases were searched for [clinical trials, original research articles, meta-analyses, and reviews], English-language articles published from [2012] to the present. Articles that were [Articles that did not meet these criteria were excluded] excluded from the analysis. FINDINGS: Several studies have found that low serum levels of vitamin D (< 20 ng/mL) are associated with increased exacerbations, increased airway inflammation, decreased lung function, and poor prognosis in asthmatic patients. Results from in vitro and in vivo studies in animals and humans have suggested that supplementation with vitamin D may ameliorate several hallmark features of asthma. However, the findings obtained from clinical trials are controversial and do not unequivocally support a beneficial role of vitamin D in asthma. Largely, interventional studies in children, pregnant women, and adults have primarily found little to no effect of vitamin D supplementation on improved asthma symptoms, onset, or progression of the disease. This could be related to the severity of the disease process and other confounding factors. IMPLICATIONS: Despite the conflicting data obtained from clinical trials, vitamin D deficiency may influence the inflammatory response in the airways. Further studies are needed to determine the exact mechanisms by which vitamin D supplementation may induce antiinflammatory effects.

Toll-like receptors, triggering receptor expressed on myeloid cells family members and receptor for advanced glycation end-products in allergic airway inflammation.

Asthma is a chronic disorder of the airways characterized by cellular infiltration, airway hyper-responsive and airway inflammation. Innate immune cells are the first line of defense against endogenous and exogenous signals in the airways and as such possess a diverse array of pattern recognition receptors. Toll-like receptors are crucial sentinels which when activated, can either promote or ameliorate the inflammatory response in predisposed individuals. The recently discovered triggering receptor expressed on myeloid cells family members are emerging mediators of inflammation. These receptors are believed to modulate inflammatory responses by collaborating with classic PRRs. Endogenous signals like HMGB-1, signaling through the receptor for advanced glycation end products, also promotes inflammation, however, its contribution to inflammation in the airways is not well known. Here, we discuss the role of each receptor in airway inflammation and highlight potential synergistic mechanisms, which contribute to disease pathogenesis in allergic asthma.

The impact of vitamin D on asthmatic human airway smooth muscle.

Asthma is a chronic heterogeneous disorder, which involves airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling. The airway smooth muscle (ASM) bundle regulates the broncho-motor tone and plays a critical role in AHR as well as orchestrating inflammation. Vitamin D deficiency has been linked to increased severity and exacerbations of symptoms in asthmatic patients. It has been shown to modulate both immune and structural cells, including ASM cells, in inflammatory diseases. Given that current asthma therapies have not been successful in reversing airway remodeling, vitamin D supplementation as a potential therapeutic option has gained a great deal of attention. Here, we highlight the potential immunomodulatory properties of vitamin D in regulating ASM function and airway inflammation in bronchial asthma.

Vitamin D Supplementation Reduces Induction of Epithelial-Mesenchymal Transition in Allergen Sensitized and Challenged Mice.

Asthma is a chronic disease of the lung associated with airway hyperresponsiveness (AHR), airway obstruction and airway remodeling. Airway remodeling involves differentiation of airway epithelial cells into myofibroblasts via epithelial-mesenchymal transition (EMT) to intensify the degree of subepithelial fibrosis. EMT involves loss in E-cadherin with an increase in mesenchymal markers, including vimentin and N-cadherin. There is growing evidence that vitamin D has immunomodulatory and anti-inflammatory properties. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we examined the contribution of vitamin D on the AHR, airway inflammation and expression of EMT markers in the airways of mice sensitized and challenged with a combination of clinically relevant allergens, house dust mite, ragweed, and Alternaria (HRA). Female Balb/c mice were fed with vitamin D-sufficient (2000 IU/kg) or vitamin D-supplemented (10,000 IU/kg) diet followed by sensitization with HRA. The density of inflammatory cells in the bronchoalveolar lavage fluid (BALF), lung histology, and expression of EMT markers by immunofluorescence were examined. Vitamin D-supplementation decreased AHR, airway inflammation in the BALF and the features of airway remodeling compared to vitamin D-sufficiency in HRA-sensitized and -challenged mice. This was accompanied with increased expression of E-cadherin and decreased vimentin and N-cadherin expression in the airways. These results indicate that vitamin D may be a beneficial adjunct in the treatment regime in allergic asthma.