TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

Whitehead, Gregory S.; Thomas, Seddon Y.; Shalaby, Karim H.; Nakano, Keiko; Moran, Timothy P.; Ward, James M.; Flake, Gordon P.; Nakano, Hideki; Cook, Donald N.

doi:10.1172/jci90890

Cited by 37 publications

(53 citation statements)

References 56 publications

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“…Because children spend the vast majority of their lives indoors, it is likely that exposures within the home environment influence allergic disease development . Within the home, children are exposed to a variety of immunostimulatory molecules, including allergens and microbial products, which can act as adjuvants in the respiratory tract and promote allergic sensitization to inhaled antigens . While indoor environmental exposures are known to contribute to wheezing and asthma inception in children, there is increasing evidence that the home environment may also impact food allergy development .…”

Section: Discussionmentioning

confidence: 99%

“…58 Within the home, children are exposed to a variety of immunostimulatory molecules, including allergens and microbial products, which can act as adjuvants in the respiratory tract and promote allergic sensitization to inhaled antigens. 36,41,42,45 While indoor environmental exposures are known to contribute to wheezing and asthma inception in children, 59 there is increasing evidence that the home environment may also impact food allergy development. 9,60,61 Although levels of peanut allergen in the home have been positively associated with peanut sensitization, it is likely that immunogenic agents within the indoor environment also influence PA development.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the bioactivity of indoor dust has been associated with aeroallergen sensitization in children at risk for allergy . We have previously shown that indoor dust extracts can programme lung cDCs to induce Th2 responses to inhaled antigens, resulting in the development of allergic airway inflammation upon subsequent inhalational allergen challenge . Whether adjuvants in indoor dust can also promote the development of allergy to environmental food allergens is unknown.…”

Section: Introductionmentioning

confidence: 99%

“…37 We have previously shown that indoor dust extracts can programme lung cDCs to induce Th2 responses to inhaled antigens, resulting in the development of allergic airway inflammation upon subsequent inhalational allergen challenge. 42,45 Whether adjuvants in indoor dust can also promote the development of allergy to environmental food allergens is unknown. To address this question, we developed an animal model that mimics inhalational exposure to environmental peanut allergen.…”

Section: Introductionmentioning

confidence: 99%

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Indoor dust acts as an adjuvant to promote sensitization to peanut through the airway

Smeekens

Immormino

Balogh

et al. 2019

Clin Experimental Allergy

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Background There is growing evidence that environmental peanut exposure through non‐oral routes, including the skin and respiratory tract, can result in peanut sensitization. Environmental adjuvants in indoor dust can promote sensitization to inhaled antigens, but whether they contribute to peanut allergy development is unclear. Objective We investigated whether indoor dust promotes airway sensitization to peanut and peanut allergy development in mice. Methods Female and male C57BL/6J mice were exposed via the airways to peanut, indoor dust extract, or both for 2 weeks. Mice were then challenged with peanut and assessed for anaphylaxis. Peanut‐specific immunoglobulins, peanut uptake by lung conventional dendritic cells (cDCs), lung innate cytokines, and T cell differentiation in lung‐draining lymph nodes were quantified. Innate cytokine production by primary human bronchial epithelial cells exposed to indoor dust was also determined. Results Inhalational exposure to low levels of peanut in combination with indoor dust, but neither alone, resulted in production of peanut‐specific IgE and development of anaphylaxis upon peanut challenge. Indoor dust triggered production of innate cytokines in murine lungs and in primary human bronchial epithelial cells. Additionally, inhaled indoor dust stimulated maturation and migration of peanut‐laden lung type 1 cDCs to draining lymph nodes. Inhalational exposure to peanut and indoor dust induced peanut‐specific T helper 2 cell differentiation and accumulation of T follicular helper cells in draining lymph nodes, which were associated with increased B cell numbers and peanut‐specific immunoglobulin production. Conclusions & clinical relevance Indoor dust promotes airway sensitization to peanut and development of peanut allergy in mice. Our findings suggest that environmental adjuvants in indoor dust may be determinants of peanut allergy development in children.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Indoor dust acts as an adjuvant to promote sensitization to peanut through the airway

Smeekens

Immormino

Balogh

et al. 2019

Clin Experimental Allergy

Self Cite

View full text Add to dashboard Cite

show abstract

“…Commonly, inflammatory infiltration and hypertrophy of airway epithelial cells can induce airway wall thickening and trachea narrowing. The previous studies have proposed that inflammation-mediated airway lesion weakens mucosal movement and increases adhesion protein secretion, which subsequently increases sputum viscosity (Whitehead et al, 2017). In this forward cycle of inflammation occurrence conditions, the defect in sputum obstruction is also responsible for severe cough (Demarche et al, 2016).…”

Section: Introductionmentioning

confidence: 98%

Suhuang Antitussive Capsules-Ameliorative Effects on LPS-Induced Sputum Obstruction in Mice Through Promoting HGF Secretion

et al. 2019

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Sputum obstruction is one of common cough complications, which is tightly associated with airway inflammation. Suhuang antitussive capsule (SH Capsule), a classic traditional Chinese medicine prescription, has been used for the treatment of post-cold cough and cough variant asthma in the long clinical application. This study aims to investigate the effects and underlying mechanisms of SH Capsule on LPS-induced sputum obstruction in mice. The results showed that SH Capsule effectively promoted the tracheal phenol red output and mucociliary clearance. SH Capsule also alleviated airway inflammationmediated mucin 5AC (MUC5AC) level through EGFR-ERK signaling. A further in vivo analysis showed that HGF inhibitor SU11274 abrogated the effects of SH Capsule on MUC5AC, well demonstrating that HGF was required for the beneficial effects of SH Capsule on expectoration in vivo. Moreover, SH Capsule promoted HGF secretion in a colon-dependent manner, which reached lung tissues via blood circulation. Collectively, this study provided new pharmacological data for clinical use of SH Capsule, and proposed a novel mechanism by which SH Capsule was pharmacologically promising for treating sputum obstruction.

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Neuropilin‐2 regulates airway inflammation in a neutrophilic asthma model

Immormino

Jania

Tilley

et al. 2021

Immunity Inflam & Disease

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Background: Asthma is a heterogenous disease that can be classified into eosinophilic (type 2-high) and noneosinophilic (type 2-low) endotypes. The type 2-low endotype of asthma can be characterized by the presence of neutrophilic airway inflammation that is poorly responsive to corticosteroids. Dysregulated innate immune responses to microbial products including Tolllike receptor (TLR) ligands have been associated with the pathogenesis of neutrophilic asthma. The key molecules that regulate inflammatory responses in individuals with neutrophilic asthma remain unclear. We previously reported that the immunoregulatory receptor neuropilin-2 (NRP2) is expressed by murine and human alveolar macrophage (AM) and suppresses lipopolysaccharide (LPS)-induced neutrophilic airway inflammation.Methods: Here, we investigated the immunoregulatory role of NRP2 in a mouse model of neutrophilic asthma.Results: We found that TLR ligands, but not T helper 2 (Th2)-promoting adjuvants, induced NRP2 expression by AM. Using an LPS-mediated model of neutrophilic asthma, we demonstrate that NRP2 was increased in AM and other lung antigen-presenting cells following airway challenge with antigen. Conditional deletion of NRP2 in myeloid cells exacerbated airway inflammation in a neutrophilic asthma model. In contrast, myeloid-specific ablation of NRP2 did not affect airway inflammation in a Th2-mediated eosinophilic asthma model. Myeloid-specific ablation of NRP2 did not affect Th1/Th17 responses to inhaled antigens or expression of neutrophil chemokines but rather resulted in impaired efferocytosis by AM, which is necessary for effective resolution of airway inflammation. Conclusion: Our findings suggest that NRP2 is a negative regulator of airway inflammation associated with neutrophilic asthma.

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TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

Cited by 37 publications

References 56 publications

Indoor dust acts as an adjuvant to promote sensitization to peanut through the airway

Indoor dust acts as an adjuvant to promote sensitization to peanut through the airway

Suhuang Antitussive Capsules-Ameliorative Effects on LPS-Induced Sputum Obstruction in Mice Through Promoting HGF Secretion

Neuropilin‐2 regulates airway inflammation in a neutrophilic asthma model

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