Palzer Kim-Alicia, Bolduan Vanessa, Lakus Jelena, Tubbe Ingrid, Montermann Evelyn, Clausen Björn E, Bros Matthias, Pautz Andrea
Department of Pharmacology, University Medical Center of the Johannes Gutenberg-University, Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
Inflamm Res. 2025 Mar 17;74(1):54. doi: 10.1007/s00011-025-02024-5.
Asthma is a chronic inflammatory disease characterized by dysregulated cytokine expression. The RNA-binding protein KSRP reduces the expression of several pro-inflammatory mediators. Therefore, we investigated whether KSRP modulates Th2-associated immune responses in vivo in an ovalbumin-induced (OVA) allergic asthma model in C57BL/6 KSRP-deficient mice (KSRP).
Asthma severity in OVA-immunized wild type or KSRP mice was determined by airway hyperresponsiveness (AHR), structural changes of lung tissue, and OVA-specific antibody production. Cytokine expression in bronchoalveolar lavage fluid (BALF) was measured by Cytometric Bead Array (CBA) analysis. Cellular signaling pathways involved in KSRP-mediated effects in asthma pathogenesis were analyzed in vitro in cell culture models using specific inhibitors.
KSRP deficiency exacerbates OVA-induced allergic asthma compared to wild type mice, as indicated by increased AHR, more severe lung damage, goblet cell hyperplasia and increased OVA-specific antibody production. CBA analyses confirmed, that KSRP deficiency enhances IL-4, IL-5 and IL-13 production in BALF. The effect of KSRP on Th2-associated cytokine expression appears to be mediated by modulation of the STAT6 and NFAT signaling pathway rather than by inhibiting the stability of cytokine-encoding mRNA species.
Our data demonstrate that KSRP dampens Th2 immune cell activity and therefore seems to be important for the pathogenesis of Th2-mediated diseases.
哮喘是一种以细胞因子表达失调为特征的慢性炎症性疾病。RNA结合蛋白KSRP可降低多种促炎介质的表达。因此，我们在C57BL/6 KSRP基因缺陷小鼠（KSRP）的卵清蛋白诱导（OVA）过敏性哮喘模型中，研究了KSRP在体内是否调节Th2相关免疫反应。
通过气道高反应性（AHR）、肺组织结构变化和OVA特异性抗体产生，确定OVA免疫的野生型或KSRP小鼠的哮喘严重程度。采用细胞计数珠阵列（CBA）分析测定支气管肺泡灌洗液（BALF）中的细胞因子表达。在细胞培养模型中使用特异性抑制剂，体外分析哮喘发病机制中KSRP介导作用所涉及的细胞信号通路。
与野生型小鼠相比，KSRP基因缺陷加剧了OVA诱导的过敏性哮喘，表现为AHR增加、肺损伤更严重、杯状细胞增生以及OVA特异性抗体产生增加。CBA分析证实，KSRP基因缺陷增强了BALF中IL-4、IL-5和IL-13的产生。KSRP对Th2相关细胞因子表达的影响似乎是通过调节STAT6和NFAT信号通路介导的，而不是通过抑制细胞因子编码mRNA种类的稳定性。
我们的数据表明，KSRP可抑制Th2免疫细胞活性，因此似乎对Th2介导疾病的发病机制很重要。
