Airway epithelial TSLP production of TLR2 drives type 2 immunity in allergic airway inflammation

Lv, Jiajia; Yu, Qianying; Lv, Jie; Di, Caixia; Lin, Xinhua; Su, Wenyu; Wu, Min; Xia, Zhenwei

doi:10.1002/eji.201847663

Cited by 41 publications

(38 citation statements)

References 48 publications

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“…The present study used OVA model, which has been the most widely used pre-clinical allergic asthma model and recapitulates many of the hallmarks of allergic asthma in humans, however, bio-models offer other allergen-induced allergic model, such as house dust mite (HDM), Alternaria, papain and IL-33, with each mimicking the major features of human asthma. When OVA, HDM, or Alternaria was given via inhalation or intranasally, each of them can be recognized and sensed by TLRs reportedly, especially TLR2 (40). Similarly, intranasally given IL-33 is reported can induce direct stimulation of TLR2 on ILC2s (39).…”

Section: Discussionmentioning

confidence: 97%

TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation

Zhao

Xie

et al. 2020

Front. Immunol.

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Toll-like receptor 2 (TLR2) is suggested to initiate the activation of NLRP3 inflammasome, and considered to be involved in asthma. The findings that melatonin modulates TLRs-mediated immune responses, together with the suppressing effect of TLRs on endogenous melatonin synthesis, support the possibility that a feedback loop exists between TLRs system and endogenous melatonin synthesis. To determine whether TLR2-melatonin feedback loop exists in allergic airway disease and regulates NLRP3 inflammasome activity, wild-type (WT) and TLR2 −/− mice were challenged with OVA to establish allergic airway disease model. Following OVA challenge, WT mice exhibited increased-expression of TLR2, activation of NLRP3 inflammasome and marked airway inflammation, which were all effectively inhibited in the TLR2 −/− mice, indicating that TLR2-NLRP3 mediated airway inflammation. Meanwhile, melatonin biosynthesis was reduced in OVA-challenged WT mice, while such reduction was notably rescued by TLR2 deficiency, suggesting that TLR2-NLRP3-mediated allergic airway inflammation was associated with decreased endogenous melatonin biosynthesis. Furthermore, addition of melatonin to OVA-challenged WT mice pronouncedly ameliorated airway inflammation, decreased TLR2 expression and NLRP3 inflammasome activation, further implying that melatonin in turn inhibited airway inflammation via suppressing TLR2-NLRP3 signal. Most interestingly, although melatonin receptor antagonist luzindole significantly reduced the protein expressions of ASMT, AANAT and subsequent level of melatonin in OVA-challenged TLR2 −/− mice, it exhibited null effect on leukocytes infiltration, Th2-cytokines production and NLRP3 activity. These results indicate that a TLR2-melatonin feedback loop regulates NLRP3 inflammasome activity in allergic airway inflammation, and melatonin may be a promising therapeutic medicine for airway inflammatory diseases such as asthma.

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Section: Discussionmentioning

confidence: 97%

TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation

Zhao

Xie

et al. 2020

Front. Immunol.

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“…In addition, TSLP derived from epithelial cells also plays an important role in the initiation of allergic inflammatory induction 31,32 . Epithelial cells were activated by external stimulus (such as allergens, microorganisms, air pollutants, etc.)…”

Section: Discussionmentioning

confidence: 99%

Frontline Science: Two flavonoid compounds attenuate allergic asthma by regulating epithelial barrier via G protein-coupled estrogen receptor: Probing a possible target for allergic inflammation

Yuan

Chen

et al. 2020

Journal of Leukocyte Biology

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Allergic asthma is a common chronic lung inflammatory disease and seriously influences public health. We aim to investigate the effects of formononetin (FMN) and calycosin (CAL), 2 flavonoids in Radix Astragali, on allergic asthma and elucidate possible therapeutic targets. A house dust mite (HDM)‐induced allergic asthma mouse model and TNF‐α and Poly(I:C) co‐stimulated human bronchial epithelial cell line (16HBE) were performed respectively in vivo and in vitro. The role of G protein‐coupled estrogen receptor (GPER) was explored by its agonist, antagonist, or GPER small interfering RNA (siGPER). E‐cadherin, occludin, and GPER were detected by western blotting, immunohistochemistry, or immunofluorescence. The epithelial barrier integrity was assessed by trans‐epithelial electric resistance (TEER). Cytokines were examined by enzyme‐linked immunosorbent assay (ELISA). The results showed that flavonoids attenuated pulmonary inflammation and hyperresponsiveness in asthmatic mice. These flavonoids significantly inhibited thymic stromal lymphopoietin (TSLP), increased occludin and restored E‐cadherin in vivo and in vitro. The effects of flavonoids on occludin and TSLP were not interfered by ICI182780 (estrogen receptor antagonist), while blocked by G15 (GPER antagonist). Furthermore, compared with PPT (ERα agonist) and DPN (ERβ agonist), G1 (GPER agonist) significantly inhibited TSLP, up‐regulated occludin, and restored E‐cadherin. siGPER and TEER assays suggested that GPER was pivotal for the flavonoids on the epithelial barrier integrity. Finally, G1 attenuated allergic lung inflammation, which could be abolished by G15. Our data demonstrated that 2 flavonoids in Radix Astragali could alleviate allergic asthma by protecting epithelial integrity via regulating GPER, and activating GPER might be a possible therapeutic strategy against allergic inflammation.

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“…Another study using the HDM model demonstrated that IL‐37 could suppress the induced concentrations of Th2 and asthma‐related cytokines IL‐4, IL‐6 and IL‐13 in lung homogenate of humanized acute allergic asthmatic mice . TSLP affects the development of Th2 immune responses at multiple stages through its effects on DCs and CD4 + T cells . We previously demonstrated that the neutralization of TSLP with an anti‐TSLP monoclonal antibody inhibited HDM‐induced Th2 responses .…”

Section: Discussionmentioning

confidence: 99%

IL‐37 alleviates house dust mite‐induced chronic allergic asthma by targeting TSLP through the NF‐κB and ERK1/2 signaling pathways

et al. 2019

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Interleukin (IL)-37 has been described as a negative regulator of immune responses and is critical for asthma pathogenesis, but the mechanisms behind the protective role of IL-37 against allergic asthma are less well understood. We show here that IL-37 administered intranasally inhibited house dust mite (HDM)-induced chronic airway eosinophilic inflammation, goblet cell hyperplasia, peribronchial collagen deposition and airway hyperresponsiveness (AHR) to methacholine. In contrast to a weakened Th2 response in the lung that was characterized by the downregulation of Th2-associated cytokines and chemokines in IL-37-treated mice, IL-37 has no effect on relevant markers of systemic Th2 immune including serum immunoglobulins expression and in vitro production of Th2-associated cytokines by splenocytes on HDM recall. We demonstrated that the production of thymic stromal lymphopoietin (TSLP) in the lung tissue was associated with IL-37. Importantly, compared with IL-37 alone, TSLP coadministration with IL-37 restored HDM-induced airway inflammation and structural alterations, increased AHR to methacholine and promoted Th2-associated cytokine production. We further found that IL-37 inhibited the induction of TSLP expression by the main antigen of house dust mite, Der p1, by suppressing NF-jB and extracellular signal regulated kinase 1/2 (ERK1/2) activation in human bronchial epithelial (16-HBE) cells in vitro. These data highlight the importance of TSLP in IL-37-mediated protective role in asthma. IL-37 might represent a useful innovative and alternative therapy to control TSLP production in the airway.

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Airway epithelial TSLP production of TLR2 drives type 2 immunity in allergic airway inflammation

Cited by 41 publications

References 48 publications

TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation

TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation

Frontline Science: Two flavonoid compounds attenuate allergic asthma by regulating epithelial barrier via G protein-coupled estrogen receptor: Probing a possible target for allergic inflammation

IL‐37 alleviates house dust mite‐induced chronic allergic asthma by targeting TSLP through the NF‐κB and ERK1/2 signaling pathways

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