Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation

Manni, Michelle L.; Mandalapu, Sivanarayana; McHugh, Kevin J.; Elloso, M. Merle; Dudas, Paul L.; Alcorn, John F.

doi:10.4049/jimmunol.1501531

Cited by 42 publications

(35 citation statements)

References 57 publications

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“…33 Further, co-transfer of T H 2 and T H 17 cells together induced steroid-resistant disease with mixed eosinophilic/neutrophilic inflammation, AHR and mucus hypersecretion. 34 These findings in mouse models demonstrate the key importance of T H cell polarization in regulating the type of inflammation in the lung, and provide evidence that T H 1/ T H 17-skewed responses can induce steroid-resistant inflammatory and pathogenic pathways. T cell polarization secondary to lung infection may also explain steroid resistance observed in infection-induced exacerbation models (described below).…”

Section: Steroid Resistancementioning

confidence: 66%

Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation

et al. 2017

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Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the majority of asthma patients, treatments for individuals with severe asthma are often ineffective. Mouse models are useful to identify mechanisms underlying disease pathogenesis and for the preclinical assessment of new therapies. In fact, existing mouse models have contributed significantly to our understanding of allergic/eosinophilic phenotypes of asthma and facilitated the development of novel targeted therapies (e.g. anti-IL-5 and anti-IgE). These therapies are effective in relevant subsets of severe asthma patients. Unfortunately, non-allergic/noneosinophilic asthma, steroid resistance and disease exacerbation remain areas of unmet clinical need. No mouse model encompasses all features of severe asthma. However, mouse models can provide insight into pathogenic pathways that are relevant to severe asthma. In this review, as examples, we highlight models relevant to understanding steroid resistance, chronic tissue remodelling and disease exacerbation. Although these models highlight the complexity of the immune pathways that may underlie severe asthma, they also provide insight into new potential therapeutic approaches.

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Section: Steroid Resistancementioning

confidence: 66%

Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation

et al. 2017

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“…Manni ML, et al . found that in patients with neutrophil-dominant severe asthma, decreased FEV1 could be associated with both positive and negative changes in lung compliance, suggesting that there is a disconnect between airway inflammation, AHR, and lung compliance (50,51). Thus, lung stiffening may be mechanistically distinct from methacholine responsiveness.…”

Section: Discussionmentioning

confidence: 99%

STAT6 Regulates the Development of Eosinophilic versus Neutrophilic Asthma in Response to Alternaria alternata

Valladao

Frevert

Koch³

et al. 2016

The Journal of Immunology

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Human asthma is a heterogeneous disease characterized by the expression of both Th2 and Th17 cytokines. In vitro and in vivo studies have shown a reciprocal regulation between Th2 and Th17 pathways, suggesting a potential induction of neutrophil-promoting Th17 inflammation in the absence of a Th2 response. Alternaria alternata is a clinically relevant allergen that is associated with severe and fatal asthma exacerbations. Exposure to A. alternata is characterized by a predominant Th2 response, but can also induce the production of factors associated with Th17 responses (e.g., CXCL8) from epithelial cells. Using a mouse model, we found that wild-type mice develop an eosinophilic Th2 airway disease in response to A. alternata exposure, while IL-4-, IL-13-, and STAT6-deficient mice exhibit a primarily neutrophilic response. Neutrophilic asthma in STAT6−/− mice was accompanied by elevated lung levels of TNF-α, CXCL1, CXCL2, and CXCL5, and was steroid-resistant. Neutralization of Th17 signaling only partially reduced neutrophil numbers and total airway inflammation. Airway neutrophilia developed in RAG-deficient and CD4-depleted Balb/c mice, suggesting that the suppression of neutrophil responses is dependent on Th2 cytokine production by T cells and that airway neutrophilia is primarily an innate response to allergen. These results highlight the importance of combination therapies for treatment of asthma and establish a role for factors other than IL-17 as targets for neutrophilic asthma.

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“…Naïve mouse T cells were isolated from the spleens of OTII mice using CD4 + CD62L + selection beads (Miltenyi) (18). Bone marrow dendritic cells from C57BL/6 or STAT1−/− mice were pulsed with heat-killed MRSA or vehicle for 24 hours.…”

Section: Methodsmentioning

confidence: 99%

STAT1 Is Required for Suppression of Type 17 Immunity during Influenza and Bacterial Superinfection

et al. 2017

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Influenza is an annual, global health care concern. Secondary bacterial pneumonia is a severe complication associated with primary influenza virus infection, often resulting in critical morbidity and mortality. Our laboratory has identified influenza-induced suppression of anti-bacterial Type 17 immunity as a mechanism for enhanced susceptibility to bacterial super-infection. We have shown that influenza-induced type I interferon impairs Type 17 activation. STAT1 is a transcription factor involved in interferon signaling, shared by type I, II, and III interferon. In this work, we investigated the role of STAT1 signaling during influenza, methicillin-resistant Staphylococcus aureus (MRSA) super-infection. STAT1−/− mice had increased morbidity and airway inflammation compared to control mice during influenza mono-infection. Despite this worsened anti-viral response, STAT1−/− mice were protected from super-infection bacterial burden and mortality compared to controls. Type 17 immune activation was increased in lymphocytes in STAT1−/− mice during super-infection. The elevation in Type 17 immunity was not related to increased IL-23 production, as type I interferon could inhibit IL-23 expression in a STAT1 independent manner. STAT1−/− antigen presenting cells were inherently biased towards Type 17 polarization compared to control cells. Further, STAT1−/− dendritic cells produced attenuated IL-6 and TNFα upon heat-killed S. aureus stimulation compared to control. Overall, these data indicate that STAT1 signaling plays a detrimental role in influenza, MRSA super-infection by controlling the magnitude of Type 17 immune activation.

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Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation

Cited by 42 publications

References 57 publications

Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation

Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation

STAT6 Regulates the Development of Eosinophilic versus Neutrophilic Asthma in Response to Alternaria alternata

STAT1 Is Required for Suppression of Type 17 Immunity during Influenza and Bacterial Superinfection

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