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Published on: May 2, 2018
Macrophage Sprouty4 deficiency diminishes sepsis-induced acute lung injury in mice
Rong Chen1, Chen Cao2, Huimin Liu1
1Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Objective:
Inflammation and oxidative stress play critical roles in sepsis-induced acute lung injury (ALI). Sprout4 (Spry4) is involved in regulating inflammation and tissue injury; however, its role and mechanism in sepsis-induced ALI remain elusive.
Methods:
Macrophage-specific Spry4 knockout (Spry4MKO), transgenic (Spry4MTG) mice and matched control littermates were generated and exposed to cecum ligation and puncture (CLP) surgery to establish bacterial sepsis-induced ALI. Bone marrow-derived macrophages (BMDMs) from Spry4MKO or Spry4MTG mice were isolated and subjected to lipopolysaccharide (LPS) stimulation to further validate the role of Spry4 in vitro. To verify the necessity of AMP-activated protein kinase (AMPK), Spry4 and AMPK double knockout mice and compound C were used in vivo and in vitro. BMDMs were treated with STO-609 to inhibit calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2).
Results:
We found that macrophage Spry4 was increased in CLP mice and positively correlated with sepsis-induced ALI. Macrophage Spry4 deficiency prevented, while macrophage Spry4 overexpression exacerbated sepsis-induced inflammation, oxidative stress and ALI in mice and BMDMs. Mechanistic studies revealed that macrophage Spry4 deficiency alleviated sepsis-induced ALI through activating CaMKK2/AMPK pathway.
Conclusion:
Our study identify macrophage Spry4 as a promising predictive and therapeutic target of sepsis-induced ALI.
Insights
Macrophage Sprout4 (Spry4) is elevated in sepsis-induced acute lung injury (ALI). Inhibiting Spry4 in macrophages protects against ALI by activating the CaMKK2/AMPK pathway, identifying Spry4 as a therapeutic target.
Area of Science:
- Immunology
- Pulmonology
- Molecular Biology
Background:
- Sepsis-induced acute lung injury (ALI) involves inflammation and oxidative stress.
- The precise role and mechanism of Sprout4 (Spry4) in sepsis-induced ALI are not well understood.
Purpose of the Study:
- To investigate the role and mechanism of macrophage Spry4 in sepsis-induced ALI.
- To determine if Spry4 is a potential therapeutic target for sepsis-induced ALI.
Main Methods:
- Generated macrophage-specific Spry4 knockout (Spry4MKO) and transgenic (Spry4MTG) mice.
- Induced sepsis-induced ALI using cecum ligation and puncture (CLP) surgery.
- Utilized bone marrow-derived macrophages (BMDMs) for in vitro validation and investigated the CaMKK2/AMPK pathway.
Main Results:
- Macrophage Spry4 expression increased and correlated with ALI severity in CLP mice.
- Spry4 deficiency in macrophages protected against sepsis-induced ALI, inflammation, and oxidative stress.
- Spry4 overexpression exacerbated these conditions, and deficiency activated the CaMKK2/AMPK pathway.
Conclusions:
- Macrophage Spry4 plays a critical role in sepsis-induced ALI.
- Spry4 is identified as a potential predictive and therapeutic target for sepsis-induced ALI.
