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Role of Atypical MAPK p38 Signaling in the Progression of Influenza A-Induced Acute Lung Injury
Jeremy C Burton1, Denise L Fahey2, Fredejah T Royer1
1Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, USA.
Abstract:
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.
Insights
Blocking atypical p38 signaling via TAB1 interaction reduces lung injury and accelerates recovery from influenza A infection. This host-directed approach targets inflammation, not viral replication, offering a novel therapeutic strategy for acute lung injury.
Area of Science:
- Immunology
- Molecular Biology
- Pulmonary Medicine
Background:
- Mitogen-activated protein kinase (MAPK) p38 is implicated in acute lung injury (ALI) pathology.
- Atypical p38 signaling, involving Tumor Growth Factor β Activated Kinase 1 (TAK1) Binding Protein 1 (TAB1), is linked to pathological responses but unstudied in ALI.
- Targeting atypical p38 signaling presents a potential therapeutic strategy for pulmonary injury.
Purpose of the Study:
- To investigate the role of atypical p38 signaling in influenza A-induced lung injury.
- To evaluate the therapeutic potential of blocking TAB1-p38 interaction in a mouse model of ALI.
Main Methods:
- Utilized a genetic knock-in mouse model to disrupt the TAB1-p38 interaction.
- Induced lung injury using influenza A infection.
- Assessed lung injury severity, histopathology, weight loss, recovery time, and immune cell recruitment (monocytes).
Main Results:
- Blocking TAB1-p38 interaction significantly reduced weight loss and accelerated recovery from influenza A-induced lung injury.
- Histopathological scores of lung injury were decreased early during infection.
- Earlier recruitment of monocytes to the lungs was observed.
- These effects were independent of viral replication and infectivity.
Conclusions:
- Atypical p38 signaling, mediated by TAB1, is a key driver of host-induced pulmonary injury during influenza infection.
- Blocking the TAB1-p38 interaction represents a promising host-directed therapeutic strategy for acute lung injury.
- This approach targets inflammation rather than viral replication, offering a novel avenue for ALI treatment.
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