The secreted airway mucus cell protein chloride channel regulator, calcium-activated 1, CLCA1, plays a role in inflammatory respiratory diseases via as yet unidentified pathways. For example, deficiency of CLCA1 in a mouse model of acute pneumonia resulted in reduced cytokine expression with less leukocyte recruitment and the human CLCA1 was shown to be capable of activating macrophages in vitro. Translation of experimental data between human and mouse models has proven problematic due to several CLCA species-specific differences. We therefore characterized activation of macrophages by CLCA1 in detail in solely murine ex vivo and in vitro models. Only alveolar but not bone marrow-derived macrophages freshly isolated from C57BL6/J mice increased their expression levels of several pro-inflammatory and leukotactic cytokines upon CLCA1 stimulation. Among the most strongly regulated genes, we identified the host-protective and immunomodulatory airway mucus component BPIFA1, previously unknown to be expressed by airway macrophages. Furthermore, evidence from an in vivo Staphylococcus aureus pneumonia mouse model suggests that CLCA1 may also modify BPIFA1 expression in airway epithelial cells. Our data underscore and specify the role of mouse CLCA1 in inflammatory airway disease to activate airway macrophages. In addition to its ability to upregulate cytokine expression which explains previous observations in the Clca1-deficient S. aureus pneumonia mouse model, modulation of BPIFA1 expression expands the role of CLCA1 in airway disease to involvement in more complex downstream pathways, possibly including liquid homeostasis, airway protection, and antimicrobial defense.

中文翻译：

---

可溶性粘液成分CLCA1调节鼠肺泡巨噬细胞中白细胞趋化因子和BPIFA1的表达，但不调节骨髓衍生巨噬细胞中的白细胞因子。

分泌的气道粘液细胞蛋白氯通道调节剂，钙激活的1，CLCA1，通过尚未确定的途径在炎性呼吸道疾病中起作用。例如，急性肺炎小鼠模型中CLCA1的缺乏导致细胞因子表达降低，白细胞募集减少，并且人类CLCA1被证明能够在体外激活巨噬细胞。由于几种CLCA物种特异性差异，已证明人与小鼠模型之间实验数据的转换存在问题。因此，我们在单独的鼠离体和体外模型中详细描述了由CLCA1激活巨噬细胞的特征。从C57BL6 / J小鼠新鲜分离的仅肺泡而不是骨髓来源的巨噬细胞会在CLCA1刺激下增加其几种促炎和白细胞因子的表达水平。在调节最强的基因中，我们鉴定了宿主保护性和免疫调节性气道粘液成分BPIFA1，以前未知由气道巨噬细胞表达。此外，来自体内金黄色葡萄球菌肺炎小鼠模型的证据表明，CLCA1还可能修饰气道上皮细胞中BPIFA1的表达。我们的数据强调并指定了小鼠CLCA1在炎症性气道疾病中激活气道巨噬细胞的作用。除了上调细胞因子表达的能力可以解释先前在Clca1缺陷型金黄色葡萄球菌肺炎小鼠模型中观察到的现象外，对BPIFA1表达的调节还扩大了CLCA1在气道疾病中的作用，使其参与了更复杂的下游途径，可能包括液体稳态，气道保护和抗菌防御。