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.
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