Inhaled delivery of recombinant interferon-lambda restores allergic inflammation after development of asthma by controlling Th2- and Th17-cell-mediated immune responses.

Remarkable progress has recently been achieved to identify the biological function and potential value of novel therapeutic targets for the effective control of allergic asthma. Interferon (IFN)-λ has been suggested to restrict chronic inflammation in the lungs of asthmatic mice and we sought to determine the contribution of IFN-λ as an asthma therapeutic. We show that inhaled IFN-λ can restrict Th2 and Th17 inflammation in the lungs of asthmatic mice, accompanied with alteration of IL-10 secretion. BALB/C mice were used for an asthmatic mouse model with OVA. Recombinant IFN-λs (IFN-λ2: 2 µg, IFN-λ3: 2 µg) were inoculated into asthmatic mice after OVA challenge by intranasal delivery. Lungs of asthmatic mice were severely inflamed, with extensive inflammatory cell infiltration and increased goblet cell metaplasia with higher total lung resistance. Transcription of IL-4, IL-5, IL-13, and IL-17A was significantly higher until five days after the final OVA challenge. Asthmatic mice were administered recombinant IFN-λ via inhalation three times after the last challenge and the asthmatic mice showed improvement in lung histopathologic findings, and total lung resistance was maintained under normal range. IFN-λ inhalation exhibited significant decreases in Th2 and Th17 cytokine levels, and the populations of Th2 and Th17 cells were recovered from the lungs of asthmatic mice. Additionally, increase in IL-10 secretion from CD4 + Th cells population was observed in response to inhaled delivery of IFN-λ along with alterations in Th2 and Th17 cell-derived inflammation. Our findings show that inhaled delivery of IFN-λ can restrict airway inflammation in the lungs of asthmatic mice by controlling Th2- and Th17-mediated responses accompanied by regulation of IL-10 secretion even after asthma development.

Symbiotic microbiome Staphylococcus aureus from human nasal mucus modulates IL-33-mediated type 2 immune responses in allergic nasal mucosa.

BACKGROUND: The host-microbial commensalism can shape the innate immune responses in respiratory mucosa and nasal microbiome also modulates front-line immune mechanism in the nasal mucosa. Inhaled allergens encounter the host immune system first in the nasal mucosa, and microbial characteristics of nasal mucus directly impact the mechanisms of initial allergic responses in nasal epithelium. However, the roles of the nasal microbiome in allergic nasal mucosa remain uncertain. We sought to determine the distribution of nasal microbiomes in allergic nasal mucosa and elucidate the interplay between nasal microbiome Staphylococcus species and Th2 cytokines in allergic rhinitis (AR) models. RESULTS: Staphylococcus aureus (AR-SA) and S. epidermidis (AR-SE) were isolated from the nasal mucosa of patients with AR. The influence of nasal microbiome Staphylococcus species on allergic nasal mucosa was also tested with in vitro and in vivo AR models. Pyrosequencing data showed that colonization by S. epidermidis and S. aureus was more dominant in nasal mucus of AR subjects. The mRNA and protein levels of IL-33 and TSLP were significantly higher in AR nasal epithelial (ARNE) cells which were cultured from nasal mucosa of AR subjects, and exposure of ARNE cells to AR-SA reduced IL-33 mRNA and secreted protein levels. Particularly, ovalbumin-driven AR mice inoculated with AR-SA by intranasal delivery exhibited significantly reduced IL-33 in their nasal mucosa. In the context of these results, allergic symptoms and Th2 cytokine levels were significantly downregulated after intranasal inoculation of AR-SA in vivo AR mice. CONCLUSION: Colonization by Staphylococcus species was more dominant in allergic nasal mucosa, and nasal commensal S. aureus from subjects with AR mediates anti-allergic effects by modulating IL-33-dependent Th2 inflammation. The results demonstrate the role of host-bacterial commensalism in shaping human allergic inflammation.

The influence of interferon-lambda on restricting Middle East Respiratory Syndrome Coronavirus replication in the respiratory epithelium.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe respiratory in human with high mortality and it has been a challenge to determine optimum treatment for MERS-CoV-induced respiratory infection. Here, we observed the distribution of MERS-CoV receptors using human respiratory mucosa and also evaluated the contribution of interferon-lambdas (IFN-λs) in response to MERS-CoV infection using in vitro normal human nasal epithelial (NHNE) and bronchial epithelial (NHBE) cells. We found that the gene and protein expression of DPPIV, MERS-CoV receptor, were more dominantly located in nasal and bronchial epithelium although human nasal mucosa exhibited relatively lower DPPIV expression than lung parenchymal tissues. The quantitative mRNA level of the MERS-CoV envelope (upE) gene was significantly induced in MERS-CoV-infected cultured NHNE and NHBE cells until 3 days after infection. The induction of IFNs was identified in NHNE and NHBE cells after MERS-CoV infection and IFN-λs were predominantly increased in MERS-CoV-infected respiratory epithelial cells. Inoculation of IFN-λs to NHNE and NHBE cells suppressed MERS-CoV replication and in particular, IFN-λ4 showed a strong therapeutic effect in reducing MERS-CoV infection with higher induction of IFN-stimulated genes. Thus, IFN-λ has a decisive function in the respiratory epithelium that greatly limits MERS-CoV replication, and may be a key cytokine for better therapeutic outcomes against MERS-CoV infection in respiratory tract.

Inhaled delivery of Interferon-lambda restricts epithelial-derived Th2 inflammation in allergic asthma.

The possibility has been suggested that interferon (IFN)-λs can be induced rapidly for restricting respiratory viral infection in asthmatic mice and may modulate Th2-related immune responses that underlie the pathogenesis of asthma. We sought to determine the in vivo contribution of IFN-λs on decrease of Th2 cytokines in the respiratory tract of in vivo asthma. Lungs of asthmatic mice were severely inflamed, with extensive inflammatory cell infiltration and increased goblet cell metaplasia with higher total lung resistance. The mean protein levels of TSLP and IL-33 from BAL fluid of asthmatic mice were significantly higher until 7 days. Following the collection of lung tissue of 20 asthmatic mice, TSLP and IL-33 gene expressions inversely correlated with mRNA levels of IFN-λ2/3. Asthmatic mice were administered recombinant IFN-λ2/3 via the intranasal route and the mRNA levels of IFN-stimulated genes were elevated to an even greater extent in the lung tissue of the mice without intranasal IFN-λ2/3. Asthma-related histopathologic lung inflammation was significantly improved and total lung resistance was maintained within normal range in IFN-λ2/3-treated asthmatic mice. Moreover, IFN-λ2/3-treated asthmatic mice exhibited significant decrease of secreted protein levels of TSLP and IL-33 in the BAL fluid until 7 days after IFN administration. The current data provide compelling evidence that the compensation of IFN-λs can restrict the secretion of epithelial-derived Th2 cytokines, accompanied with reduced asthmatic immunopathology and IFN-λs are critical for limiting Th2-mediated allergic responses in allergic asthma.

Anti-photoaging properties of the phosphodiesterase 3 inhibitor cilostazol in ultraviolet B-irradiated hairless mice.

We investigated whether cilostazol, an activator of cyclic adenosine monophosphate (cAMP)-dependent intracellular signaling, could inhibit ultraviolet B (UVB) irradiation-induced photoaging in HR-1 hairless mice. Cilostazol decreased wrinkle formation and skin thickness in UVB-irradiated mice, as well as increased staining of collagen fibers and inhibition of reactive oxygen species (ROS) formation in the skin. Moreover, the proteolytic activities of gelatinase matrix metalloproteinase (MMP)-9 and collagenase MMP-3 were significantly decreased in UVB-irradiated mice treated with cilostazol. Western blotting showed that UVB-induced activation of p38 mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-κB was significantly inhibited by cilostazol, whereas the activation of Akt was significantly enhanced by cilostazol. Confirmation of localized protein expression in the skin revealed marked p38 MAPK and NF-κB activation that was mainly detected in the dermis. Marked Akt activation was mainly detected in the epidermis. Our results suggest that cilostazol may have anti-photoaging effects on UVB-induced wrinkle formation by maintaining the extracellular matrix density in the dermis, which occurs via regulation of ROS and related p38 MAPK and NF-κB signaling, and subsequent down-regulation of MMPs. Therefore, cilostazol may protect against photoaging-induced wrinkle formation.