Phospholipase Cγ2 (PLCγ2) Is Key Component in Dectin-2 Signaling Pathway, Mediating Anti-fungal Innate Immune Responses

Dekai Zhang,Sara Gorjestani,Demin Wang,Xin Lin,Bing Tang,Mei Yu

doi:10.1074/jbc.m111.307389

Abstract

C-type lectin receptors (CLRs) such as Dectin-2 function as pattern recognition receptors to sense fungal infection. However, the signaling pathways induced by these receptors remain largely unknown. Previous studies suggest that the CLR-induced signaling pathway may utilize similar signaling components as the B cell receptor-induced signaling pathway. Phospholipase Cγ2 (PLCγ2) is a key component in B cell receptor signaling, but its role in other signaling pathways has not been fully characterized. Here, we show that PLCγ2 functions downstream of Dectin-2 in response to the stimulation by the hyphal form of Candida albicans, an opportunistic pathogenic fungus. Using PLCγ2- and PLCγ1-deficient macrophages, we found that the lack of PLCγ2, but not PLCγ1, impairs cytokine production in response to infection with C. albicans. PLCγ2 deficiency results in the defective activation of NF-κB and MAPK and a significantly reduced production of reactive oxygen species following fungal challenge. In addition, PLCγ2-deficient mice are defective in clearing C. albicans infection in vivo. Together, these findings demonstrate that PLCγ2 plays a critical role in CLR-induced signaling pathways, governing antifungal innate immune responses.

Highlights

Phospholipase C␥2 (PLC␥2) Is Involved in Dectin-2-induced Signaling Pathway— To determine whether C. albicans can activate PLC␥2 through Dectin-2 receptor in macrophages, we examined PLC␥2 phosphorylation in bone marrow-derived macrophages (BMDMs) after infecting them with C. albicans hyphae
Because both Dectin-1 and Dectin-2 have been shown to be involved in antifungal innate immune response, we determined whether Dectin-1 and Dectin-2 are required for C. albicans hyphaeinduced PLC␥2 activation using BMDMs treated with a specific shRNA to Dectin-2 or BMDMs from Dectin-1 knock-out mice
Consistent with previous findings that Dectin-2 but not Dectin-1 is involved in C. albicans hyphae-induced signal transduction, we found that PLC␥2 activation was dependent on Dectin-2 but not Dectin-1 (Fig. 1, B and C)

Summary

Background

Conclusion: PLC␥2 is a key component in Dectin-2 signaling pathway, mediating immune responses against fungal infection. PLC␥2-deficient mice are defective in clearing C. albicans infection in vivo Together, these findings demonstrate that PLC␥2 plays a critical role in CLR-induced signaling pathways, governing antifungal innate immune responses. Recent studies on Dectin-1-deficient mice suggest that there may be other redundant receptors mediating C. albicans infection-induced immune responses [15, 16]. The signaling pathways induced by Dectin-2 following C. albicans infection are not fully defined, previous studies indicate that stimulation of Dectin-2 as well as Dectin-1 by the cell wall components of C. albicans can activate the spleen tyrosine kinase (Syk) [10, 17, 18]. Using PLC␥1- and PLC␥2-deficient mice, we show that PLC␥2 but not PLC␥1 plays an essential role in the immune responses to C. albicans infection by inducing expression of cytokines and generating reactive oxygen species

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION