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TRPV4 Regulates the Macrophage Metabolic Response to Limit Sepsis-induced Lung Injury
Erica M Orsini1, Sanjoy Roychowdhury2, Mahesha Gangadhariah2
1Department of Pulmonary and Critical Care, Integrated Hospital Care Institute, and.
Abstract:
Sepsis is a systemic inflammatory response that requires effective macrophage metabolic functions to resolve ongoing inflammation. Previous work showed that the mechanosensitive cation channel, transient receptor potential vanilloid 4 (TRPV4), mediates macrophage phagocytosis and cytokine production in response to lung infection. Here, we show that TRPV4 regulates glycolysis in a stiffness-dependent manner by augmenting macrophage glucose uptake by GLUT1. In addition, TRPV4 is required for LPS-induced phagolysosome maturation in a GLUT1-dependent manner. In a cecal slurry mouse model of sepsis, TRPV4 regulates sepsis-induced glycolysis as measured by BAL fluid (BALF) lactate and sepsis-induced lung injury as measured by BALF total protein and lung compliance. TRPV4 is necessary for bacterial clearance in the peritoneum to limit sepsis-induced lung injury. It is interesting that BALF lactate is increased in patients with sepsis compared with healthy control participants, supporting the relevance of lung cell glycolysis to human sepsis. These data show that macrophage TRPV4 is required for glucose uptake through GLUT1 for effective phagolysosome maturation to limit sepsis-induced lung injury. Our work presents TRPV4 as a potential target to protect the lung from injury in sepsis.
Insights
Transient Receptor Potential Vanilloid 4 (TRPV4) channels regulate macrophage metabolism and glucose uptake, crucial for resolving sepsis. Targeting TRPV4 may protect lungs from sepsis-induced injury.
Area of Science:
- Immunology
- Cell Biology
- Physiology
Background:
- Sepsis involves systemic inflammation requiring macrophage metabolic functions.
- Transient Receptor Potential Vanilloid 4 (TRPV4) channels influence macrophage responses in lung infections.
- Macrophage metabolic reprogramming is critical for sepsis resolution.
Purpose of the Study:
- To investigate the role of TRPV4 in regulating macrophage glycolysis and glucose uptake.
- To determine TRPV4's involvement in phagolysosome maturation and bacterial clearance during sepsis.
- To assess the therapeutic potential of targeting TRPV4 in sepsis-induced lung injury.
Main Methods:
- Investigated TRPV4's regulation of glucose uptake via GLUT1 in macrophages.
- Utilized a cecal slurry mouse model of sepsis.
- Measured glycolysis (BALF lactate), lung injury (BALF total protein, lung compliance), and bacterial clearance.
Main Results:
- TRPV4 regulates glycolysis in a stiffness-dependent manner by enhancing macrophage glucose uptake through GLUT1.
- TRPV4 is essential for LPS-induced phagolysosome maturation in a GLUT1-dependent manner.
- In a sepsis model, TRPV4 controlled glycolysis, lung injury, and bacterial clearance, with elevated BALF lactate in human sepsis patients.
Conclusions:
- Macrophage TRPV4 is vital for glucose uptake via GLUT1, enabling phagolysosome maturation and limiting sepsis-induced lung injury.
- TRPV4 plays a key role in regulating macrophage metabolism during sepsis.
- TRPV4 emerges as a potential therapeutic target for protecting the lungs against sepsis-related damage.
