Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signaling

Author:

Yuan Chuang,Ai Kelong,Xiang Menghua,Xie Chengliang,Zhao Mingyi,Wu MingORCID,Li Hongli,Wu Yueren,Cao Yueqing,Li Can,Zhong Yanjun,Pei Xiaomeng,Law Helen Ka Wai,Gao LiqianORCID,Xiao QicaiORCID,Yang XinyuORCID

Abstract

AbstractSepsis is a life-threatening syndrome with disturbed host responses to severe infections, accounting for the majority of death in hospitalized patients. However, effective medicines are currently scant in clinics due to the poor understanding of the exact underlying mechanism. We previously found that blocking caspase-11 pathway (human orthologs caspase-4/5) is effective to rescue coagulation-induced organ dysfunction and lethality in sepsis models. Herein, we screened our existing chemical pools established in our lab using bacterial outer membrane vesicle (OMV)-challenged macrophages, and found 7-(diethylamino)-1-hydroxy-phenothiazin-3-ylidene-diethylazanium chloride (PHZ-OH), a novel phenothiazinium-based derivative, was capable of robustly dampening caspase-11-dependent pyroptosis. The in-vitro study both in physics and physiology showed that PHZ-OH targeted AP2-associated protein kinase 1 (AAK1) and thus prevented AAK1-mediated LPS internalization for caspase-11 activation. By using a series of gene-modified mice, our in-vivo study further demonstrated that administration of PHZ-OH significantly protected mice against sepsis-associated coagulation, multiple organ dysfunction, and death. Besides, PHZ-OH showed additional protection on Nlrp3−/− and Casp1/ mice but not on Casp11−/−, Casp1/11−/−, Msr1−/−, and AAK1 inhibitor-treated mice. These results suggest the critical role of AAK1 on caspase-11 signaling and may provide a new avenue that targeting AAK1-mediated LPS internalization would be a promising therapeutic strategy for sepsis. In particular, PHZ-OH may serve as a favorable molecule and an attractive scaffold in future medicine development for efficient treatment of bacterial sepsis.

Funder

Natural Science Foundation of Hunan Province

National Natural Science Foundation of China

Natural Science Foundation of Guangdong Province

Shenzhen Science and Technology Innovation Commission

Guangzhou Science and Technology Program key projects

Hunan Natural Science Fund for Distinguished Young Scholars

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology

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