Emerging evidence indicates that several mammalian C-type lectin receptors (CLRs) in innate immune cells function as pattern recognition receptors (PRRs) for sensing fungal infections, and trigger multiple signaling cascades leading to expression of various pro- inflammatory cytokines and anti-microbial proteins. In our previous studies, we have found that Dectin-2 and Dectin-3, two CLRs, form a heterodimeric complex on innate immune cells and function as a PRR for sensing fungal infection. Although many studies have been focused on characterizing the activation event of CLR signaling in response to fungal infection, it is not very clear whether CLR proteins and their signaling are negatively regulated i response to fungal infection. In our preliminary studies, we have revealed two important aspects of negative regulation of CLR signaling. First, we found that Dectin-2 and Dectin-3, two CLRs involved in sensing fungal infection, were rapidly downregulated in macrophages following fungal challenging, and this downregulation is triggered by signal-induced ubiquitination through a Cbl- b-dependent mechanism, and the ubiquitinated Dectin-2/Dectin-3 appears to be degraded through a lysosome-mediated process. Second, we found that stimulation of Dectin-2/Dectin-3 can effectively induce JNK activation, but instead of playing a positive role, JNK1 activation negatively regulates CLR-induced CD23 expression that is involved in modulating anti-fungal immune response. Therefore, based on our compelling and exciting preliminary data, we propose 1) to determine the molecular mechanism by which Cbl-b regulates the degradation of Dectin-2/Dectin-3 in response to fungal infection; and 2) to characterize the molecular mechanism by which JNK1 is negatively involved in anti-fungal immune responses. Together, these lines of investigation will characterize two important mechanisms that negatively regulate host innate immune system against fungal infection, and will provide the molecular insight for designing novel therapeutic agents by modulating host innate immune system against fungal infection.
Mammalian host sensing fungal infection is through several C-type lectin receptors (CLRs). Revealing the mechanism by which CLRs and their signaling in innate immune cells are negatively regulated in response to fungal infection will provide the molecular insight for designing therapeutic strategies to treat fungal infection. Therefore, the proposed studies in this application will provide molecular insight for designing therapeutic agents that may strengthen host innate immune system against fungal infection.
|Zhao, Xueqiang; Guo, Yahui; Jiang, Changying et al. (2017) JNK1 negatively controls antifungal innate immunity by suppressing CD23 expression. Nat Med 23:337-346|
|Li, Xun; Cullere, Xavier; Nishi, Hiroshi et al. (2016) PKC-? activation in neutrophils promotes fungal clearance. J Leukoc Biol 100:581-8|
|Wang, Tingting; Pan, Deng; Zhou, Zhicheng et al. (2016) Dectin-3 Deficiency Promotes Colitis Development due to Impaired Antifungal Innate Immune Responses in the Gut. PLoS Pathog 12:e1005662|
|Cao, Li; Qin, Xing; Peterson, Matthew R et al. (2016) CARD9 knockout ameliorates myocardial dysfunction associated with high fat diet-induced obesity. J Mol Cell Cardiol 92:185-95|
|Zhu, Le-Le; Luo, Tian-Ming; Xu, Xia et al. (2016) E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity. J Exp Med 213:1555-70|
|Joo, Donghyun; Tang, Yong; Blonska, Marzenna et al. (2016) Regulation of Linear Ubiquitin Chain Assembly Complex by Caspase-Mediated Cleavage of RNF31. Mol Cell Biol 36:3010-3018|
|Jiang, Changying; Zhou, Zhicheng; Quan, Yanping et al. (2016) CARMA3 Is a Host Factor Regulating the Balance of Inflammatory and Antiviral Responses against Viral Infection. Cell Rep 14:2389-401|
|Lee, Ellen J; Brown, Brieanna R; Vance, Emily E et al. (2016) Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye. J Immunol 196:3148-58|
|Atif, Shaikh M; Lee, Seung-Joo; Li, Lin-Xi et al. (2015) Rapid CD4+ T-cell responses to bacterial flagellin require dendritic cell expression of Syk and CARD9. Eur J Immunol 45:513-24|
|Drummond, Rebecca A; Collar, Amanda L; Swamydas, Muthulekha et al. (2015) CARD9-Dependent Neutrophil Recruitment Protects against Fungal Invasion of the Central Nervous System. PLoS Pathog 11:e1005293|