CLEC5A is critical in Pseudomonas aeruginosa–induced NET formation and acute lung injury
Pei-Shan Sung, … , Cheng-Hsun Chiu, Shie-Liang Hsieh
Pei-Shan Sung, … , Cheng-Hsun Chiu, Shie-Liang Hsieh
Published September 1, 2022
Citation Information: JCI Insight. 2022;7(18):e156613. https://doi.org/10.1172/jci.insight.156613.
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Research Article Infectious disease Inflammation

CLEC5A is critical in Pseudomonas aeruginosa–induced NET formation and acute lung injury

Abstract

Pseudomonas aeruginosa is one of the most common nosocomial infections worldwide, and it frequently causes ventilator-associated acute pneumonia in immunocompromised patients. Abundant neutrophil extracellular traps (NETs) contribute to acute lung injury, thereby aggravating ventilator-induced lung damage. While pattern recognition receptors (PRRs) TLR4 and TLR5 are required for host defense against P. aeruginosa invasion, the PRR responsible for P. aeruginosa–induced NET formation, proinflammatory cytokine release, and acute lung injury remains unclear. We found that myeloid C-type lectin domain family 5 member A (CLEC5A) interacts with LPS of P. aeruginosa and is responsible for P. aeruginosa–induced NET formation and lung inflammation. P. aeruginosa activates CLEC5A to induce caspase-1–dependent NET formation, but it neither causes gasdermin D (GSDMD) cleavage nor contributes to P. aeruginosa–induced neutrophil death. Blockade of CLEC5A attenuates P. aeruginosa–induced NETosis and lung injury, and simultaneous administration of anti-CLEC5A mAb with ciprofloxacin increases survival rate and decreases collagen deposition in the lungs of mice challenged with a lethal dose of P. aeruginosa. Thus, CLEC5A is a promising therapeutic target to reduce ventilator-associated lung injury and fibrosis in P. aeruginosa–induced pneumonia.

Authors

Pei-Shan Sung, Yu-Chun Peng, Shao-Ping Yang, Cheng-Hsun Chiu, Shie-Liang Hsieh

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Figure 7

CLEC5A is a potential therapeutic target in P. aeruginosa–induced collagen deposition.

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CLEC5A is a potential therapeutic target in P. aeruginosa–induced collag...
WT mice were intratracheally injected with a sublethal dose (LD90) of P. aeruginosa Xen41 (1 × 106 PFU) and injected with isotype control (mIgG1, 100 μg per mouse, i.v.), anti-mCLEC5A mAb (clone 4A12D5, 100 μg per mouse, i.v.), ciprofloxacin (Cip, 4 mg/kg, i.p.), or anti-mCLEC5A mAb combined with ciprofloxacin at 15 hours after infection. Ciprofloxacin was given every 12 hours. (A) Collagen deposition was observed by Picrosirius red staining, and the images were captured using light microscopy (upper panel) and polarized light microscopy (lower panel). Scale bar: 200 μm. (B) Collagen deposition was quantified from polarized light images using MetaMorph software and presented as area (μm2) of collagen. Data are mean ± SEM from Xen41 + Cip (n = 10) and Xen41 + Cip + anti-CLEC5A mAb (n = 6). Statistical analysis was calculated with unpaired and nonparametric Student’s t test with Mann-Whitney U test. ***P < 0.001.