Mohammed Zahraa, McHale Cody, Kubinak Jason L, Dryer Stuart, Gomez Gregorio
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States.
Molecular Targeted Therapeutics Laboratory, Levine Cancer Institute, Charlotte, NC, United States.
Front Allergy. 2022 Apr 18;3:835776. doi: 10.3389/falgy.2022.835776. eCollection 2022.
MicroRNA-155 (miR-155) has been implicated in IgE-dependent allergic disease including asthma and atopic dermatitis. A few roles for miR-155 have been described in mast cells and some specifically related to IgE receptor signaling, but it is not completely understood. Here, we demonstrate by miRNA seq profiling and quantitative RT-PCR that miR-155 expression is significantly increased in human skin-derived mast cells (SMCs) and mouse bone marrow-derived mast cells (BMMCs) following FcεRI crosslinking with antigen. We demonstrate that FcεRI-induced expression of () was significantly inhibited in miR-155 knockout (KO) BMMCs whereas () expression and leukotriene C4 (LTC) biosynthesis, and degranulation were unaffected. FcεRI-induced cytokine production (TNF, IL-6, and IL-13) from miR-155 KO BMMCs was also significantly diminished. Correspondingly, Akt phosphorylation, but not protein expression, was inhibited in the absence of miR-155 whereas p38 and p42/44 were unaffected. Interesting, lipopolysaccharide (LPS)-induced cytokine production was increased in miR-155 KO BMMCs. Together, these data demonstrate that miR-155 specifically targets the FcεRI-induced prostaglandin and cytokine pathways, but not the leukotriene or degranulation pathways, in mast cells. The data further suggest that miR-155 acts indirectly by targeting a repressor of expression and a phosphatase that normally blocks Akt phosphorylation. Overall, this study reveals the role of miR-155 as a positive regulator of mast cell function.
微小RNA-155（miR-155）与包括哮喘和特应性皮炎在内的IgE依赖性过敏性疾病有关。已经在肥大细胞中描述了miR-155的一些作用，其中一些作用与IgE受体信号传导特别相关，但尚未完全了解。在这里，我们通过miRNA序列分析和定量RT-PCR证明，在用抗原交联FcεRI后，人皮肤来源的肥大细胞（SMC）和小鼠骨髓来源的肥大细胞（BMMC）中miR-155表达显著增加。我们证明，在miR-155基因敲除（KO）的BMMC中，FcεRI诱导的（）表达被显著抑制，而（）表达、白三烯C4（LTC）生物合成和脱颗粒不受影响。来自miR-155 KO BMMC的FcεRI诱导的细胞因子产生（TNF、IL-6和IL-13）也显著减少。相应地，在没有miR-155的情况下，Akt磷酸化受到抑制，但蛋白质表达不受影响，而p38和p42/44不受影响。有趣的是，在miR-155 KO BMMC中，脂多糖（LPS）诱导的细胞因子产生增加。总之，这些数据表明，miR-155在肥大细胞中特异性靶向FcεRI诱导的前列腺素和细胞因子途径，但不靶向白三烯或脱颗粒途径。数据进一步表明，miR-155通过靶向（）表达的抑制因子和通常阻断Akt磷酸化的磷酸酶间接发挥作用。总体而言，这项研究揭示了miR-155作为肥大细胞功能正调节因子的作用。
