Immunology and Microbiology Department, University of Colorado School of Medicine, Aurora, CO, United States.
Department of Biomedical Research, National Jewish Health, Denver, CO, United States.
Front Immunol. 2020 Dec 8;11:590266. doi: 10.3389/fimmu.2020.590266. eCollection 2020.
Kinase activity plays an essential role in the regulation of immune cell defenses against pathogens. The protein kinase CK2 (formerly casein kinase II) is an evolutionarily conserved kinase with hundreds of identified substrates. CK2 is ubiquitously expressed in somatic and immune cells, but the roles of CK2 in regulation of immune cell function remain largely elusive. This reflects the essential role of CK2 in organismal development and limited prior work with conditional CK2 mutant murine models. Here, we generated mice with a conditional (floxed) allele of , which encodes the catalytic CK2α subunit of CK2. When crossed to -cre mice, excision of sequence impaired CK2α expression in myeloid cells but failed to detectably alter myeloid cell development. By contrast, deficiency for CK2α increased inflammatory myeloid cell recruitment, activation, and resistance following systemic (Lm) infection. Results from mixed chimera experiments indicated that CK2α deficiency in only a subset of myeloid cells was not sufficient to reduce bacterial burdens. Nor did cell-intrinsic deficiency for CK2α suffice to alter accumulation or activation of monocytes and neutrophils in infected tissues. These data suggest that CK2α expression by -expressing cells promotes inflammatory and anti-bacterial responses through effects . Our results highlight previously undescribed suppressive effects of CK2 activity on inflammatory myeloid cell responses and illustrate that cell-extrinsic effects of CK2 can shape inflammatory and protective innate immune responses.
激酶活性在调节免疫细胞抵御病原体的防御中起着至关重要的作用。蛋白激酶 CK2(以前称为酪蛋白激酶 II)是一种进化上保守的激酶,具有数百种已鉴定的底物。CK2 在体细胞和免疫细胞中广泛表达,但 CK2 在调节免疫细胞功能中的作用在很大程度上仍未被揭示。这反映了 CK2 在机体发育中的重要作用以及用条件性 CK2 突变体小鼠模型进行的有限前期工作。在这里,我们生成了具有条件性(floxed)等位基因的小鼠,该基因编码 CK2 的催化 CK2α 亚基。当与 -cre 小鼠杂交时,序列的缺失破坏了髓样细胞中的 CK2α 表达,但未能检测到髓样细胞发育的改变。相比之下,CK2α 的缺失增加了全身性 (Lm)感染后炎症性髓样细胞的募集、激活和耐药性。混合嵌合体实验的结果表明,仅在髓样细胞亚群中缺乏 CK2α 不足以降低细菌负荷。细胞内 CK2α 的缺乏也不足以改变感染组织中单核细胞和中性粒细胞的积累或激活。这些数据表明,表达细胞的 CK2α 表达通过 促进炎症和抗细菌反应。我们的结果强调了 CK2 活性对炎症性髓样细胞反应的先前未描述的抑制作用,并表明 CK2 的细胞外效应可以塑造炎症和保护性先天免疫反应。