Burton Jeremy C, Fahey Denise L, Royer Fredejah T, Zhu Yin, Sakamoto Kaori, Zhang Duo, Watford Wendy T, Grimsey Neil J
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, USA.
Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.
FASEB J. 2025 Sep 30;39(18):e71075. doi: 10.1096/fj.202501156RR.
Mitogen-activated protein kinase (MAPK) p38 plays a key role in driving the pathology of acute lung injury (ALI), but effective therapeutic targeting remains elusive. Atypical p38 signaling, mediated by interaction with the adaptor protein Tumor Growth Factor β Activated Kinase 1 (TAK1) Binding Protein 1 (TAB1), has so far only been observed during pathological responses, representing a selective and alternative target during pulmonary injury. However, atypical signaling has not been investigated in the context of pulmonary injury and immune responses related to the onset and progression of ALI. Here, we utilized a genetic knock-in mouse to block influenza A-induced lung injury mediated by atypical signaling. We report that the loss of TAB1-p38 interaction reduces weight loss and recovery time, reduces histopathological scores associated with influenza-induced lung injury early during infection, and prompts earlier recruitment of monocytes to the lungs following infection. These results were found to be independent of viral replication and infectivity, representing the first evidence for the roles of atypical signaling as a driver of host-mediated pulmonary injury following influenza infection.
丝裂原活化蛋白激酶（MAPK）p38在急性肺损伤（ALI）的病理过程中起关键作用，但有效的治疗靶点仍难以捉摸。由与衔接蛋白肿瘤生长因子β激活激酶1（TAK1）结合蛋白1（TAB1）相互作用介导的非典型p38信号传导，迄今为止仅在病理反应中观察到，代表了肺损伤期间的一个选择性和替代性靶点。然而，尚未在与ALI的发生和进展相关的肺损伤和免疫反应背景下研究非典型信号传导。在这里，我们利用基因敲入小鼠来阻断由非典型信号传导介导的甲型流感病毒诱导的肺损伤。我们报告说，TAB1-p38相互作用的丧失减少了体重减轻和恢复时间，降低了感染早期与流感诱导的肺损伤相关的组织病理学评分，并促使感染后单核细胞更早地募集到肺部。这些结果被发现与病毒复制和传染性无关，代表了非典型信号传导作为流感感染后宿主介导的肺损伤驱动因素作用的首个证据。
