Inhibition of TLR4 inhibits allergic responses in murine allergic rhinitis by regulating the NF‑κB pathway

Xu, Haitian; Shu, Hai-Rong; Zhu, Jie; Song, Jukun

doi:10.3892/etm.2019.7631

Cited by 15 publications

(14 citation statements)

References 47 publications

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“…Intranasal administration of lidocaine. The total amount for intranasal administration is usually 20 µl (23). During the experiment, 1, 3 and 5 mg/kg/day lidocaine was intranasally administered to mice (n=10) 3 h prior to OVA challenge on days 28-34.…”

Section: Methodsmentioning

confidence: 99%

Lidocaine relieves murine allergic rhinitis by regulating the NF‑κB and p38 MAPK pathways

2022

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Allergic rhinitis (AR) is one of the most common chronic inflammatory diseases and its main feature is nasal mucositis. It has been recently revealed that lidocaine demonstrates optimal effects in the treatment of various diseases. However, a limited number of studies have examined the association between lidocaine and AR. In the present study, the AR mouse model was established to explore the effects of lidocaine in AR and to further analyze its molecular mechanism. Subsequently, different concentrations of lidocaine were provided to the animals by intranasal administration and a series of indices were assessed. The data indicated that the frequencies of mouse sneezing and nose rubbing were suppressed following an increase in lidocaine concentration. Subsequently, the number of inflammatory cells was measured. Wright's-Giemsa staining results indicated that lidocaine significantly decreased the numbers of leukocytes, eosinophils, neutrophils and lymphocytes in the nasal lavage fluid (NLF) of AR mice. In addition, the expression levels of ovalbumin (OVA)-specific immunoglobulin E (IgE), leukotriene C4 (LTC4) and certain inflammatory factors were assessed by ELISA. Lidocaine reduced OVA-specific IgE and LTC4 expression in NLF and plasma derived from AR mice. It also decreased the expression levels of IL-4, IL-5, IL-13, IL-17 and TNF-α. Lidocaine caused upregulation of IFN-γ and IL-2 expression levels. Subsequently, western blot analysis indicated that lidocaine suppressed phosphorylated (p)-p38 and p-p65 expression levels in AR mice. Collectively, the results indicated that the NF-κB and p38 MAPK signaling pathways were involved in the lidocaine-mediated relief of AR in mice. In order to further verify the association between the NF-κB and p38 MAPK signaling pathways and AR in mice, the effects of the NF-κB inhibitor IMD-0354 and the p38 MAPK inhibitor SB 203580 were assessed on AR mice. The results indicated that these two compounds exhibited similar inhibitory effects on AR mice as those noted with the use of lidocaine. These findings suggested that lidocaine represented a novel therapeutic agent for AR.

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Section: Methodsmentioning

confidence: 99%

Lidocaine relieves murine allergic rhinitis by regulating the NF‑κB and p38 MAPK pathways

2022

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“…Although a large body of research investigated the implication of TLRs, particularly TLR4, in allergic airway inflammation (19,(21)(22)(23)(24), only few studies focused specifically on pollen sources. The stimulation of epithelial cells by short ragweed pollen (Ambrosia artemisiifolia) was shown to result from a TLR4-dependent secretion of TSLP and IL-33, two key alarmins associated with the induction of Th2 responses and allergic sensitization (25).…”

Section: Introductionmentioning

confidence: 99%

Birch Pollen Induces Toll-Like Receptor 4-Dependent Dendritic Cell Activation Favoring T Cell Responses

et al. 2021

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Seasonal exposure to birch pollen (BP) is a major cause of pollinosis. The specific role of Toll-like receptor 4 (TLR4) in BP-induced allergic inflammation and the identification of key factors in birch pollen extracts (BPE) initiating this process remain to be explored. This study aimed to examine (i) the importance of TLR4 for dendritic cell (DC) activation by BPE, (ii) the extent of the contribution of BPE-derived lipopolysaccharide (LPS) and other potential TLR4 adjuvant(s) in BPE, and (iii) the relevance of the TLR4-dependent activation of BPE-stimulated DCs in the initiation of an adaptive immune response. In vitro, activation of murine bone marrow-derived DCs (BMDCs) and human monocyte-derived DCs by BPE or the equivalent LPS (nLPS) was analyzed by flow cytometry. Polymyxin B (PMB), a TLR4 antagonist and TLR4-deficient BMDCs were used to investigate the TLR4 signaling in DC activation. The immunostimulatory activity of BPE was compared to protein-/lipid-depleted BPE-fractions. In co-cultures of BPE-pulsed BMDCs and Bet v 1-specific hybridoma T cells, the influence of the TLR4-dependent DC activation on T cell activation was analyzed. In vivo immunization of IL-4 reporter mice was conducted to study BPE-induced Th2 polarization upon PMB pre-treatment. Murine and human DC activation induced by either BPE or nLPS was inhibited by the TLR4 antagonist or by PMB, and abrogated in TLR4-deficient BMDCs compared to wild-type BMDCs. The lipid-free but not the protein-free fraction showed a reduced capacity to activate the TLR4 signaling and murine DCs. In human DCs, nLPS only partially reproduced the BPE-induced activation intensity. BPE-primed BMDCs efficiently stimulated T cell activation, which was repressed by the TLR4 antagonist or PMB, and the addition of nLPS to Bet v 1 did not reproduce the effect of BPE. In vivo, immunization with BPE induced a significant Th2 polarization, whereas administration of BPE pre-incubated with PMB showed a decreased tendency. These findings suggest that TLR4 is a major pathway by which BPE triggers DC activation that is involved in the initiation of adaptive immune responses. Further characterization of these BP-derived TLR4 adjuvants could provide new candidates for therapeutic strategies targeting specific mechanisms in BP-induced allergic inflammation.

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“…It was previously found that the mRNA and protein levels of TLR4 were significantly increased in nasal mucosa of patients with pollen-induced AR [ 13 ]. TLR4 inhibition alleviated allergic responses in mice with AR [ 14 ]. Previous results indicate that TLR4 plays a vital role in AR.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of miR-224-5p alleviates allergic rhinitis in mice via the TLR4/MyD88/NF-κB pathway

Zhang

et al. 2021

Exp. Anim.

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Inflammatory allergic reaction is the main cause of allergic rhinitis (AR). Previous studies indicated that miR-224-5p was downregulated in the nasal mucosa of patients with AR, while the function of miR-224-5p in AR remains unclear. To explore this issue, AR mouse model was established using ovalbumin (OVA). For treatment group, lentivirus (LV)-miR-224-5p or its control was intranasally administrated to AR mice. miR-224-5p expression was detected by reverse transcription-quantitative PCR, followed by assessing the immunoglobulin E (IgE) level. Pathological alterations in nasal mucosa were detected using Hematoxylin-Eosin staining and Sirius red staining, followed by assessing the levels of inflammatory cells and factors. The NLRP3 inflammasome and TLR4/MyD88/NF-κB pathway were measured by Western blot, and then the relationship between miR-224-5p and toll-like receptor 4 (TLR4) was verified. The results showed that miR-224-5p was significantly decreased in nasal mucosa of AR mice. AR mice exhibited increased sneezing and nasal rubbing events, IgE level in serum, and pathological alterations in nasal mucosa, while overexpression of miR-224-5p markedly attenuated these changes. The levels of inflammatory cells in nasal lavage fluid and pro-inflammatory factors in serum and nasal mucosa were significantly increased in AR mice, which were reduced by miR-224-5p overexpression. Of note, LV-miR-224-5p treatment remarkably suppressed the activations of NLRP3 inflammasome and the TLR4/MyD88/NF-κB pathway in AR mice. Furthermore, miR-224-5p could bind to 3'-untranslated region (3'-UTR) of TLR4 and negatively regulate TLR4 level. Overall, we conclude that miR-224-5p 3 may relieve AR by negatively regulating TLR4/MyD88/NF-κB pathway, indicating that miR-224-5p may be a promising target for AR treatment.

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Inhibition of TLR4 inhibits allergic responses in murine allergic rhinitis by regulating the NF‑κB pathway

Cited by 15 publications

References 47 publications

Lidocaine relieves murine allergic rhinitis by regulating the NF‑κB and p38 MAPK pathways

Lidocaine relieves murine allergic rhinitis by regulating the NF‑κB and p38 MAPK pathways

Birch Pollen Induces Toll-Like Receptor 4-Dependent Dendritic Cell Activation Favoring T Cell Responses

Overexpression of miR-224-5p alleviates allergic rhinitis in mice via the TLR4/MyD88/NF-κB pathway

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