The NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome is an intracellular protein complex containing a nucleotide-binding oligomerization domain,leucine-rich repeats,and a pyrin domain.It i...The NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome is an intracellular protein complex containing a nucleotide-binding oligomerization domain,leucine-rich repeats,and a pyrin domain.It is a key regulator of inflammation in viral pneumonia(VP).Small-molecule inhibitors targeting various NLRP3 binding sites are advancing into early clinical trials,but their therapeutic utility is incompletely established.Xuanfei Baidu Formula(XF),clinically used for VP treatment,attenuates NLRP3 activation by hampering caspase-11 to impede polarization of pro-inflammatory macrophages in a model of lipopolysaccharide(LPS)-induced lung injury inmice.Herein,we demonstrate that XF attenuated influenza A virus(IAV)-induced lung inflammation as well as lung injury in immunocompetent(but not in macrophage-depleted)mice.RNA sequencing of sorted lung macrophages from IAV-infected mice revealed that XF inhibited activation of the NLRP3 inflammation and interleukin(IL)-1βproduction.Quantitative nuclear magnetic resonance of XF enabled us to develop XF-Comb1,a fixed-ratio combination of five bioactive compounds that recapitulated the bioactivity of XF in suppressing NLRP3 activation in macrophages in vitro and in vivo.Interestingly,XF-Comb1 inhibited assembly of the NLRP3 inflammasome through multi-site interactions with functional residues of NLRP3,apoptosis-associated speck-like protein containing caspase recruitment domain(ASC),and caspase-1.Taken together,this work advances the development of NLRP3 inhibitors by translating a complex herbal formula into defined bioactive compounds.展开更多
基金supported by the National Natural Science Foundation of China(82141201,82405164,82204878,and 32170872)the Haihe Laboratory of Modern Chinese Medicine(Research and development of a universal treatment formula for respiratory viral infections)+3 种基金the National Key Research and Development Program of China(2021YFC1712905,2021YFC1712904,2020YFA0708004,2021YFE0200300,and 2023YFC2306202)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-D-202002,ZYYCXTD-D-202001)the China Postdoctoral Science Foundation(2023M742626)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(CPSF)(GZC20231927).
文摘The NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome is an intracellular protein complex containing a nucleotide-binding oligomerization domain,leucine-rich repeats,and a pyrin domain.It is a key regulator of inflammation in viral pneumonia(VP).Small-molecule inhibitors targeting various NLRP3 binding sites are advancing into early clinical trials,but their therapeutic utility is incompletely established.Xuanfei Baidu Formula(XF),clinically used for VP treatment,attenuates NLRP3 activation by hampering caspase-11 to impede polarization of pro-inflammatory macrophages in a model of lipopolysaccharide(LPS)-induced lung injury inmice.Herein,we demonstrate that XF attenuated influenza A virus(IAV)-induced lung inflammation as well as lung injury in immunocompetent(but not in macrophage-depleted)mice.RNA sequencing of sorted lung macrophages from IAV-infected mice revealed that XF inhibited activation of the NLRP3 inflammation and interleukin(IL)-1βproduction.Quantitative nuclear magnetic resonance of XF enabled us to develop XF-Comb1,a fixed-ratio combination of five bioactive compounds that recapitulated the bioactivity of XF in suppressing NLRP3 activation in macrophages in vitro and in vivo.Interestingly,XF-Comb1 inhibited assembly of the NLRP3 inflammasome through multi-site interactions with functional residues of NLRP3,apoptosis-associated speck-like protein containing caspase recruitment domain(ASC),and caspase-1.Taken together,this work advances the development of NLRP3 inhibitors by translating a complex herbal formula into defined bioactive compounds.
