Regulation of Nasal Airway Homeostasis and Inflammation in Mice by SHP-1 and Th2/Th1 Signaling Pathways

Cho, Seok Hyun; Oh, Sun Young; Lane, Andrew P.; Lee, Joon; Oh, Min Hee; Lee, Seakwoo; Zheng, Tao; Zhu, Zhou

doi:10.1371/journal.pone.0103685

Cited by 13 publications

(7 citation statements)

References 51 publications

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“…Further analysis of the lungs in mev mice reveals a Th2-like inflammatory response, including eosinophilia, increased Th2 cytokines IL-4, IL-5, and IL-13 but not IFN-g, and increased Stat6 phosphorylation [134]. This Th2 skewing was also seen in the upper airway and nasal mucosa [135]. mev mice that also lack Stat6 or IL-4 have significantly reduced lung inflammation.…”

Section: Mast Cells and Basophilsmentioning

confidence: 88%

Shp1 function in myeloid cells

Abram

Lowell

2017

Journal of Leukocyte Biology

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The mouse was first described in 1975 as a model of systemic inflammation and autoimmunity, as a result of immune system dysregulation. The phenotype was later ascribed to mutations in the cytoplasmic tyrosine phosphatase Shp1. This phosphatase is expressed widely throughout the hematopoietic system and has been shown to impact a multitude of cell signaling pathways. The determination of which cell types contribute to the different aspects of the phenotype caused by global Shp1 loss or mutation and which pathways within these cell types are regulated by Shp1 is important to further our understanding of immune system regulation. In this review, we focus on the role of Shp1 in myeloid cells and how its dysregulation affects immune function, which can impact human disease.

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Section: Mast Cells and Basophilsmentioning

confidence: 88%

Shp1 function in myeloid cells

Abram

Lowell

2017

Journal of Leukocyte Biology

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“…Consistent with previous findings, these data show here for the first time, reductions in goblet cell formation (as indicated by PAS staining) in RSV+ neonatal lungs treated with inhaled IFNγ (16 ng/g and 60 ng/g) when compared to untreated RSV+ pups. Mounting evidence continues to support the role of IFNγ as a regulator of mucus production [ 34 – 36 ]. Determining its precise mechanism in decreasing mucus production during neonatal RSV infection is an ongoing focus of research in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

Alveolar macrophages support interferon gamma-mediated viral clearance in RSV-infected neonatal mice

et al. 2015

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BackgroundPoor interferon gamma (IFNγ) production during respiratory syncytial virus (RSV) is associated with prolonged viral clearance and increased disease severity in neonatal mice and humans. We previously showed that intra-nasal delivery of IFNγ significantly enhances RSV clearance from neonatal lungs prior to observed T-lymphocyte recruitment or activation, suggesting an innate immune mechanism of viral clearance. We further showed that alveolar macrophages dominate the RSV-infected neonatal airways relative to adults, consistent with human neonatal autopsy data. Therefore, the goal of this work was to determine the role of neonatal alveolar macrophages in IFNγ-mediated RSV clearance.MethodsClodronate liposomes, flow cytometry, viral plaque assays, and histology were used to examine the role of alveolar macrophages (AMs) and the effects of intra-nasal IFNγ in RSV infected neonatal Balb/c mice. The functional outcomes of AM depletion were determined quantitatively by viral titers using plaque assay. Illness was assessed by measuring reduced weight gain.ResultsAM activation during RSV infection was age-dependent and correlated tightly with IFNγ exposure. Higher doses of IFNγ more efficiently stimulated AM activation and expedited RSV clearance without significantly affecting weight gain. The presence of AMs were independently associated with improved RSV clearance, whereas AM depletion but not IFNγ exposure, significantly impaired weight gain in RSV-infected neonates.ConclusionWe show here for the first time, that IFNγ is critical for neonatal RSV clearance and that it depends, in part, on alveolar macrophages (AMs) for efficient viral clearing effects. Early reductions in viral burden are likely to have profound short- and long-term immune effects in the vulnerable post-natally developing lung environment. Studies are ongoing to elucidate the pathologic effects associated with early versus delayed RSV clearance in developing neonatal airways.

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“…IL-27 inhibits IFN-γ-induced autophagy by concomitant induction of the JAK/PI3K/Akt/mTOR cascade, in addition, Th2 cytokines IL-4 and IL-13 can also inhibit IFN-γ-induced autophagy [14, 81, 123]. Conversely, IFN-γ is considered as a regulator to Th2 responses, and deletion of IFN-γ gene strongly triggers Th2 cytokines secretion in inflammatory diseases [124]. Type III IFNs (IFN-λs) share some common characteristics and therapeutic benefits with type I IFNs, but the effects on cellular autophagy are different from type I IFNs.…”

Section: The Relationship Between Autophagy and Cytokinesmentioning

confidence: 99%

“…A study has indicated that IL-10 inhibits angiotensin II-induced pathological autophagy by activating PI3K/Akt/mTORC1 signaling and promoting Bcl2-Beclin1 interaction that could attenuate the anti-apoptosis effect; however, pharmacological or molecular inhibitors of Akt and mTORC1 signaling can weaken IL-10-inhibited Ang II-induced autophagy [137]. Furthermore, IL-4 and IL-13 signaling also activate PI3K signaling to activate mTORC1 in macrophage cells, and Th2 cytokines IL-4, IL-13 and IL-10 exert autophagy inhibition in most environments [124]. During monocytes–DCs differentiation and DCs survival, cytoprotective autophagy responses are essential for counteracting IL-10-triggered apoptosis, but IL-10 can strongly inhibit starvation-induced autophagy and decrease Bcl-2 levels, which indicates increased levels of Beclin-1, LC3, and mature autophagosomes and results in restricting DCs growth.…”

Section: The Relationship Between Autophagy and Cytokinesmentioning

confidence: 99%

The relationship between autophagy and the immune system and its applications for tumor immunotherapy

et al. 2019

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Autophagy is a genetically well-controlled cellular process that is tightly controlled by a set of core genes, including the family of autophagy-related genes (ATG). Autophagy is a “double-edged sword” in tumors. It can promote or suppress tumor development, which depends on the cell and tissue types and the stages of tumor. At present, tumor immunotherapy is a promising treatment strategy against tumors. Recent studies have shown that autophagy significantly controls immune responses by modulating the functions of immune cells and the production of cytokines. Conversely, some cytokines and immune cells have a great effect on the function of autophagy. Therapies aiming at autophagy to enhance the immune responses and anti-tumor effects of immunotherapy have become the prospective strategy, with enhanced antigen presentation and higher sensitivity to CTLs. However, the induction of autophagy may also benefit tumor cells escape from immune surveillance and result in intrinsic resistance against anti-tumor immunotherapy. Increasing studies have proven the optimal use of either ATG inducers or inhibitors can restrain tumor growth and progression by enhancing anti-tumor immune responses and overcoming the anti-tumor immune resistance in combination with several immunotherapeutic strategies, indicating that induction or inhibition of autophagy might show us a prospective therapeutic strategy when combined with immunotherapy. In this article, the possible mechanisms of autophagy regulating immune system, and the potential applications of autophagy in tumor immunotherapy will be discussed.

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Regulation of Nasal Airway Homeostasis and Inflammation in Mice by SHP-1 and Th2/Th1 Signaling Pathways

Cited by 13 publications

References 51 publications

Shp1 function in myeloid cells

Shp1 function in myeloid cells

Alveolar macrophages support interferon gamma-mediated viral clearance in RSV-infected neonatal mice

The relationship between autophagy and the immune system and its applications for tumor immunotherapy

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