New mechanism of regulation of innate immunity against infection by cholesterol metabolites

Under the infection of virus or bacteria, host cells can participate in anti infection through many effective ways Among them, virus infection can induce host cells to change the expression of cholesterol metabolizing enzymes and metabolites, and cholesterol metabolism can also regulate the antiviral response of host cells On December 24, influence online published the research results of cooperation between Wang Hongyan, a researcher of Molecular Cell Science Innovation Center / Institute of Biochemistry and cell biology, Chinese Academy of Sciences, and Wei bin, a professor of Shanghai University (former researcher of Wuhan Institute of viruses, Chinese Academy of Sciences) laboratory: targeting 7-dehydrocholesterol reduce integrate cholesteriol metadata and IRF3 activation to eliminate infection。 In order to find cholesterol metabolizing enzymes or corresponding natural products involved in antiviral infection, they screened liver tissues or macrophages of liver cancer patients infected with hepatitis B virus, mice infected with various types of viruses, and found that the expression of 7-dehydrocholesterol reductase (DHCR7) was significantly reduced in response to DNA virus or RNA virus infection DHCR7 is the key enzyme to convert 7-dehydrocholesterol (7-DHC) into cholesterol The patients with DHCR7 mutation have mental retardation, but it is not clear how DHCR7 regulates the function of innate immunity and antiviral infection By constructing conditional knockout mice, knockout macrophages and blocking DHCR7 enzyme activity with small molecular inhibitors, the production of IFN β mediated by viral infection can be significantly enhanced In addition, the content of 7-DHC in liver tissue infected by virus, macrophages treated with DHCR7 or its suppressor increased, and the natural product 7-DHC also promoted the anti infection function of macrophages Interestingly, tamoxifen, a chemotherapy drug used to treat breast cancer, has been approved by FDA to inhibit DHCR7 enzyme activity This study found that tamoxifen has a new function of inhibiting vesicular stomatitis virus (VSV) and zikv infection The content of 7-DHC in serum of mice treated with AY9944, an inhibitor of DHCR7, increased significantly, which protected mice against lethal dose of VSV and influenza virus (H1N1) infection Further exploration of the mechanism showed that the expression of Akt3 was very low in resting macrophages, and the expression of Akt3 was promoted by virus infection, while the activation of pi3k-akt3 was promoted by metabolite 7-DHC In addition, Akt3, as a protein kinase, directly binds to IRF3, enhances the phosphorylation of IRF3 at serine 385, promotes the formation and transfer of IRF3 dimer to the nucleus, and finally enhances the production of IFN β Akt3 knockout mice significantly reduced the production of IFN β, increased the viral load, resulting in more mouse deaths In conclusion, DHCR7, a target cholesterol metabolism pathway, can lead to the accumulation of 7-dehydrocholesterol, an upstream product, and improve IFN β and antiviral function by activating Akt3 and IRF3 This study not only provides a new drug target to resist the infection of new or highly pathogenic virus, but also provides a new idea for cholesterol metabolism reprogramming to regulate natural immunity