The innate immune response and cytokine milieu in the airway mucosa triggered by bronchial epithelial cells are crucial for the establishment or protection of cryptococcosis. In experimental cryptococcosis, Th2 immune response is associated with host susceptibility, while Th1 cells are associated with protection. Additionally, lack of IL-27 receptor alpha increases the Cryptococcus neoformans burden in the lung. Here, we evaluated the effects in vitro of the IL-4, IFN-γ or IL-27 and C. neoformans combination on human bronchial epithelial cells (BEAS-2B). BEAS-2B were stimulated with IL-4, IFN-γ or IL-27 (100  ng/mL) and/or live yeast forms of C. neoformans (multiplicities of infection (MOI) of 1-100). After 24h of infection, IL-6, CCL2 and IL-8 productions and STAT1 and STAT6 phosphorylations were evaluated. We found that cells stimulated with all cytokines (IL-4, IFN-γ or IL-27) followed by C. neoformans infection (MOI of 100) caused a reduction in IL-6 and/or CCL2 production and in STAT6 (induced by IL-4) and STAT1 (induced by IL-27 or IFN-γ) activation when compared to cells stimulated only with C. neoformans , IL-4, IFN-γ or IL-27. In vitro phagocytosis assay showed that the IL-27 and C. neoformans combination decreased the internalized fungus rate, while IL-4 and IFN-γ with C. neoformans favored fungus internalization. Association of C. neoformans with either of these cytokines promoted a higher fungal growth. Our data demonstrate that live yeast forms of C. neoformans with IL-4, IFN-γ or IL-27 induced an anti-inflammatory effect and may lead to a susceptible fungal growth environment in airway epithelium.

Non-healing wounds have a negative impact on quality of life and account for many cases of amputation and even early death among patients. Diabetic patients are the predominate population affected by these non-healing wounds. Despite the significant clinical demand, treatment with biologics has not broadly impacted clinical care. Interleukin-4 (IL-4) is a potent modulator of the immune system, capable of skewing macrophages towards a pro-regeneration phenotype (M2) and promoting angiogenesis, but can be toxic after frequent administration and is limited by its short half-life and low bioavailability. Here, we demonstrate the design and characterization of an engineered recombinant interleukin-4 construct. We utilize this collagen-binding, serum albumin-fused IL-4 variant (CBD-SA-IL-4) delivered in a hyaluronic acid (HA)-based gel for localized application of IL-4 to dermal wounds in a type 2 diabetic mouse model known for poor healing as proof-of-concept for improved tissue repair. Our studies indicate that CBD-SA-IL-4 is retained within the wound and can modulate the wound microenvironment through induction of M2 macrophages and angiogenesis. CBD-SA-IL-4 treatment significantly accelerated wound healing compared to native IL-4 and HA vehicle treatment without inducing systemic side effects. This CBD-SA-IL-4 construct can address the underlying immune dysfunction present in the non-healing wound, leading to more effective tissue healing in the clinic.
© 2023. Springer Nature Limited.

The current asthma therapies are inadequate for many patients with severe asthma. Pyrroloquinoline quinone (PQQ) is a naturally-occurring redox cofactor and nutrient that can exert a multitude of physiological effects, including anti-inflammatory and antioxidative effects. We sought to explore the effects of PQQ on allergic airway inflammation and reveal the underlying mechanisms. In vitro, the effects of PQQ on the secretion of epithelial-derived cytokines by house dust mite- (HDM-) incubated 16-HBE cells and on the differentiation potential of CD4+ T cells were investigated. In vivo, PQQ was administered to mice with ovalbumin- (OVA-) induced asthma, and lung pathology and inflammatory cell infiltration were assessed. The changes in T cell subsets and signal transducers and activators of transcription (STATs) were evaluated by flow cytometry. Pretreatment with PQQ significantly decreased HDM-stimulated thymic stromal lymphopoietin (TSLP) production in a dose-dependent manner in 16-HBE cells and inhibited Th2 cell differentiation in vitro. Treatment with PQQ significantly reduced bronchoalveolar lavage fluid (BALF) inflammatory cell counts in the OVA-induced mouse model. PQQ administration also changed the secretion of IFN-γ and IL-4 as well as the percentages of Th1, Th2, Th17, and Treg cells in the peripheral blood and lung tissues, along with inhibition the phosphorylation of STAT1, STAT3, and STAT6 while promoting that of STAT4 in allergic airway inflammation model mice. PQQ can alleviate allergic airway inflammation in mice by improving the immune microenvironment and regulating the JAK-STAT signaling pathway. Our findings suggest that PQQ has great potential as a novel therapeutic agent for inflammatory diseases, including asthma.
Copyright © 2022 Zhihui Min et al.

The traditional Chinese medicinal herb Notopterygium incisum Ting ex H.T. Chang has anti-rheumatism activity, and a mass spectrometry assay of patients' serum after administration of the herb revealed that notopterol is the most abundant component enriched. However, the functions of notopterol and its molecular target in rheumatoid arthritis (RA) treatment remain unknown. Here, we show in different RA mouse strains that both oral and intraperitoneal administration of notopterol result in significant therapeutic effects. Mechanistically, notopterol directly binds Janus kinase (JAK)2 and JAK3 kinase domains to inhibit JAK/signal transducers and activators of transcription (JAK-STAT) activation, leading to reduced production of inflammatory cytokines and chemokines. Critically, combination therapy using both notopterol and tumor necrosis factor (TNF) blocker results in enhanced therapeutic effects compared to using TNF blocker alone. We demonstrate that notopterol ameliorates RA pathology by targeting JAK-STAT signaling, raising the possibility that notopterol could be effective in treating other diseases characterized by aberrant JAK-STAT signaling pathway.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Diabetic nephropathy (DN) is a major cause of end stage kidney disease and a strong risk factor for cardiovascular diseases. Growing data show chronic inflammation plays an important role for the progression of DN. As for the immune cells, anti-inflammatory leukocytes as well as pro-inflammatory leukocytes play an important role in DN. In addition to leukocytes, renal resident cells contribute to the inflammatory process of DN. However, precise functions, phenotypes and immune balance of renal resident cells remain to be explored. Therefore, we hypothesized that the aberrant immune balance of renal resident cells contributes to the pathogenesis of DN. To explore this possibility, we performed genome-wide transcriptome profiling in mesangial cells and tubular epithelial cells (TECs), which were stimulated by high glucose (HG) and detected the expression of inflammation associated genes. HG increased the mRNA expression of oxidative stress, inflammasome and mammalian target of rapamycin (mTOR) related genes in mesangial cells. Pro-inflammatory/Th1 gene expression was upregulated, but Th2 related gene expression was downregulated in mesangial cells. In TECs, HG stimulation increased pro-inflammatory/Th1/Th2 gene expression. Phosphorylation of signaling proteins shifted towards pro-inflammatory phenotype with suppressed phosphorylation of Th2 related signaling in TECs. The data taken together indicate that HG shifts the immune balance toward pro-inflammatory/Th1 phenotype in mesangial cells and TECs, which might initiate and/or prolong inflammation, thereby resulting in diabetic nephropathy.
Copyright © 2013 Elsevier Inc. All rights reserved.