Aquaporin-9 Aggravates Lipopolysaccharides Induced Acute Lung Injury Via Facilitating M1-Like Macrophage Polarization
Aquaporin-9 Aggravates Lipopolysaccharides Induced Acute Lung Injury Via Facilitating M1-Like Macrophage Polarization
Jiajia Wan1,2, Chi Zhang3, Xiaodi Li3, Longkang Liu3, Linxiu Peng3,4, Yuejian Liu2, Yang Qiu2, Guokai Wu2, Bo Zhang3*, Yan Wang3* and Tonghui Ma3*
ABSTRACT
Alveolar macrophages (AMs) play a crucial role in orchestrating lung inflammation in acute lung injury (ALI), which largely depends upon M1-like macrophage polarization. However, the underlying regulatory mechanisms remain incompletely elucidated. The present study identified, for the first time, that aquaporin-9 (AQP9) is expressed in AMs and undergoes significant up-regulation following lipopolysaccharides (LPS) administration. AQP9 gene knockout (AQP9 KO) mice exhibited markedly attenuated alveolar hemorrhage and interstitial edema in an LPS-induced ALI model compared with wild-type (WT) littermates. The mitigated lung injury in AQP9 KO mice correlated with significantly alleviated pulmonary inflammation as indicated by significantly reduced immunofluorescent staining of CD68+ macrophages in the lungs, decreased level of the pro-inflammatory cytokine IL-6 and increased level of the anti-inflammatory cytokine IL-10 in the bronchoalveolar lavage fluid (BALF). Concurrently, mRNA levels of TNF-α and IL-1β were also significantly reduced in the lungs of LPS-induced AQP9 KO mice. Further investigation revealed that AQP9 deficiency caused defective M1-like polarization of AMs due to reduced import of extracellular hydrogen peroxide (H2O2) and impeded activation of NF-κB signaling pathway. Our findings demonstrate that AQP9 facilitates M1-like macrophage polarization by modulating plasma membrane H2O2 transport, thereby exacerbating lung inflammation in LPS-induced ALI. The study provides new insights into the regulatory mechanisms of M1-like macrophage polarization in LPS-induced ALI.
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