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Tissue-resident macrophages exacerbate lung injury after remote sterile damage
Hanhui Zhong1, Jingjing Ji2, Jinling Zhuang1
1The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
Abstract:
Remote organ injury, which is a common secondary complication of sterile tissue damage, is a major cause of poor prognosis and is difficult to manage. Here, we report the critical role of tissue-resident macrophages in lung injury after trauma or stroke through the inflammatory response. We found that depleting tissue-resident macrophages rather than disrupting the recruitment of monocyte-derived macrophages attenuated lung injury after trauma or stroke. Our findings revealed that the release of circulating alarmins from sites of distant sterile tissue damage triggered an inflammatory response in lung-resident macrophages by binding to receptor for advanced glycation end products (RAGE) on the membrane, which activated epidermal growth factor receptor (EGFR). Mechanistically, ligand-activated RAGE triggered EGFR activation through an interaction, leading to Rab5-mediated RAGE internalization and EGFR phosphorylation, which subsequently recruited and activated P38; this, in turn, promoted RAGE translation and trafficking to the plasma membrane to increase the cellular response to RAGE ligands, consequently exacerbating inflammation. Our study also showed that the loss of RAGE or EGFR expression by adoptive transfer of macrophages, blocking the function of RAGE with a neutralizing antibody, or pharmacological inhibition of EGFR activation in macrophages could protect against trauma- or stroke-induced remote lung injury. Therefore, our study revealed that targeting the RAGE-EGFR signaling pathway in tissue-resident macrophages is a potential therapeutic approach for treating secondary complications of sterile damage.
Insights
Tissue-resident macrophages critically drive lung injury following sterile damage. Targeting the receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) signaling pathway in these cells offers a potential therapeutic strategy.
Area of Science:
- Immunology
- Cell Biology
- Pathology
Background:
- Remote organ injury is a significant complication of sterile tissue damage, leading to poor patient outcomes.
- Tissue-resident macrophages play a crucial role in the inflammatory response underlying secondary organ damage.
Purpose of the Study:
- To investigate the role of tissue-resident macrophages in lung injury following sterile tissue damage.
- To elucidate the molecular mechanisms by which macrophages contribute to remote lung injury.
- To identify potential therapeutic targets for preventing or treating secondary lung injury.
Main Methods:
- Depletion of tissue-resident macrophages in mouse models of sterile injury.
- Analysis of macrophage recruitment and activation.
- Investigating the involvement of the receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) signaling pathways.
- Pharmacological inhibition and genetic manipulation of RAGE and EGFR.
Main Results:
- Depleting tissue-resident macrophages, but not blocking monocyte recruitment, attenuated lung injury.
- Circulating alarmins from distant injury sites activate lung-resident macrophages via RAGE-EGFR signaling.
- This pathway involves RAGE internalization, EGFR phosphorylation, P38 activation, and enhanced RAGE expression, leading to inflammation.
- Inhibition of RAGE or EGFR signaling protected against lung injury.
Conclusions:
- Tissue-resident macrophages are key mediators of secondary lung injury after sterile damage.
- The RAGE-EGFR signaling axis in macrophages is critical for this inflammatory response.
- Targeting the RAGE-EGFR pathway in tissue-resident macrophages presents a promising therapeutic strategy for managing remote organ complications.
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