Acute Kidney Injury Induces Lung Damage via Mitochondrial DAMPs by Activating TREM-1 and cGAS-STING Pathways

Area of Science:

• Nephrology
• Immunology
• Cell Biology

Background:

• Acute kidney injury (AKI) often leads to dysfunction in distant organs, particularly the lungs.
• Mitochondrial dysfunction and the release of mitochondrial damage-associated molecular patterns (mtDAMPs) are key drivers of inflammation in AKI.
• The precise mechanisms linking kidney injury to lung inflammation require further elucidation.

Purpose of the Study:

• To investigate the role of TREM-1 and the cGAS-STING pathway in mediating lung injury following renal ischemia-reperfusion (IR) AKI.
• To determine if inhibiting TREM-1 and cGAS-STING can mitigate mtDAMP-induced lung inflammation and cell damage.

Main Methods:

• Mice underwent renal ischemia-reperfusion (IR) injury.
• Cytokine profiling, Western Blot (WB), and Transmission Electron Microscopy (TEM) were used to analyze kidney and lung tissues.
• mtDAMPs were injected into mice, and in vitro studies used mouse macrophages and lung epithelial cells.
• Electric Cell-substrate Impedance Sensing (ECIS) assessed cell proliferation, migration, and cytotoxicity.

Main Results:

• Renal IR-AKI induced significant increases in TREM-1 and the cGAS-STING pathway in mice.
• Damaged kidney mitochondria released mtDAMPs, which triggered lung inflammation.
• Inhibition of TREM-1 and cGAS-STING pathways in vitro reduced mtDAMP-induced cytotoxicity and enhanced cell repair.
• mtDAMP injection mimicked the lung inflammatory response seen in AKI.

Conclusions:

• TREM-1 and the cGAS-STING pathway are critical mediators of lung injury secondary to AKI.
• Targeting TREM-1 and cGAS-STING presents a potential therapeutic strategy to attenuate acute lung injury in the context of IR-AKI.