MicroRNA-133b Ameliorates Allergic Inflammation and Symptom in Murine Model of Allergic Rhinitis by Targeting Nlrp3

Abstract

Background: Emerging evidences indicate that post-transcriptional regulation by microRNAs is critical in allergic rhinitis (AR) pathogenesis. MircroRNA-133b (miR-133b) was recently suggested as a potential predictor of AR. However, the in vivo effect of miR-133b on AR is unclear. Methods: AR model was established in BALB/c mice by intraperitoneal sensitization and intranasal challenge with ovalbumin (OVA). MiR-133b agomir was then intranasally administrated to mice after OVA challenge for another 7 days. The symptom of nasal rubbing and sneezing were recorded after the last OVA challenge. Nasal mucosa tissues and serum were collected. MiR-133b expression, serum OVA-specific immunoglobulin E (IgE) concentration, proinflammatory cytokines (TNF-α, IL-4, IL-5, IL-10 and IFN-γ) levels, and Nlrp3 inflammasome activation were measured by RT-PCR, ELISA, western blotting or immunohistochemistry, respectively. Histopathologic changes were evaluated using hematoxylin and eosin and Sirius red staining. The luciferase activity and protein expression of Nlrp3 were also determined. Results: MiR-133b expression was significantly decreased in nasal mucosa of AR mice, which was restored by nasal administration with miR-133b agomir. Upregulation of miR-133b markedly reduced the concentration of OVA-specific IgE, the frequencies of nasal rubbing and sneezing, and the levels of cytokines (TNF-α, IL-4, IL-5 and IFN-γ). Levels of IL-4, IL-5, IL-10 and IFN-γ produced by cervical lymph node cells were significantly lowered in miR-133b agomir-treated mice. Moreover, miR-133b also appeared to strongly attenuate pathological alterations and eosinophils and mast cells infiltration in nasal mucosa. Notably, we demonstrated for the first time that miR-133b negatively regulated Nlrp3 expression through binding with the 3’ untranslated region of Nlrp3. Consequently, infection of miR-133b in nasal mucosa remarkably suppressed the Nlrp3 inflammasome activation, as evidenced by reduced Nlrp3, Caspase-1, ASC, IL-18 and IL-1 expressions. Conclusion: MiR-133b alleviates allergic symptom in AR mice by inhibition of Nlrp3 inflammasome-meditated inflammation. These findings provide us an insight into the potential role of miR-133b in relation to AR treatment.

An update on cell intrinsic negative regulators of the NLRP3 inflammasome

“…Studies with HEK293T cells transfected with miR‐133b and a luciferase reporter conjugated to 3′UTR of murine Nlrp3 mRNA suggested that miR‐133b binds to the 3′UTR of murine Nlrp3 mRNA to negatively regulate Nlrp3 mRNA expression . Overexpression of miR‐133b in HEK293T cells reduced the protein levels of NLRP3, whereas inhibition of miR‐133b increased the protein levels of HEK293T cells in vitro . Importantly, miR‐133b inhibited NLRP3 inflammasome activation and ameliorated allergic inflammation in a mouse model of allergic rhinitis .…”

“…Several other miRs have also been implicated in regulating Nlrp3 mRNA expression in various inflammatory settings. Studies with HEK293T cells transfected with miR‐133b and a luciferase reporter conjugated to 3′UTR of murine Nlrp3 mRNA suggested that miR‐133b binds to the 3′UTR of murine Nlrp3 mRNA to negatively regulate Nlrp3 mRNA expression . Overexpression of miR‐133b in HEK293T cells reduced the protein levels of NLRP3, whereas inhibition of miR‐133b increased the protein levels of HEK293T cells in vitro .…”

Maternal Obesity in Mice Exacerbates the Allergic Inflammatory Response in the Airways of Male Offspring

“…Several lines of evidence indicate that miR-133b is relevant to the inflammatory response and lung remodeling in allergic asthma. Lower levels of circulating miR-133b have been detected in asthmatic patients [22], and its overexpression in nasal mucosa was shown to target the Nlrp3 inflammasome and reduce eosinophil infiltration and IgE, TNF-α, IL-4, IL-5 and IFN-γ levels in mice sensitized/challenged with OVA [23].…”

“…Evidence showing that miR-133b is more than only a biomarker for allergic asthma came from studies with mice demonstrating that the model of sensitization and challenge with OVA leads to a reduction in miR-133b expression in nasal mucosa. It was further demonstrated that upregulation of miR-133b with an specific agomir was able to abrogate OVA-induced increased in IgE, IL-4, IL-5 and TNF-α levels and lung eosinophil infiltration [23].…”

Protective effects of microRNA‐22‐3p against retinal pigment epithelial inflammatory damage by targeting NLRP3 inflammasome

“…Recent studies have identified that NLRP3 can be regulated by several miRNAs including miR-223 (Xie et al, 2017), miR-133b (Xiao, Jiang, Hu, & Li, 2017), miR-495 (T. Zhou et al, 2018), and miR-22 (Huang, Wei, Lin, & Huang, 2017) in various diseases. Of note, the expression pattern of miRNAs is also tissue-specific, which keeps line with the tissue-specific pathological process.…”