Cutting Edge: EPHB2 Is a Coreceptor for Fungal Recognition and Phosphorylation of Syk in the Dectin-1 Signaling Pathway

Sun, Wanwei; Wang, Heping; Hu, Huijun; Ma, Xiaojian; Zhang, Huazhi; Chen, Jianwen; Du, Yanyun; He, Ruirui; Cui, Zhenzhong; Peng, Qianwen; Wang, Chenhui

doi:10.4049/jimmunol.2001373

Cited by 8 publications

(3 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are high levels of IL-1β and IL-18 in the liver of schistosome-infected mice, and in HSC cells with highly activated NLRP3 inflammasome ( Meng et al., 2016 ). Dendritic cell-associated C-type lectin-1 (Dectin-1) is a C-type lectin-like pattern receptor that recruits and phosphorylates spleen tyrosine kinase (Syk) ( Sun W. et al., 2021 ). Activation of NLRP3 in HSCs caused by schistosome infections depends on the Dectin-1/Syk signaling pathway ( Figure 2 ), while inhibition of NLRP3 inflammasome activation significantly reduces egg granulomas and liver fibrosis ( Lu et al., 2017 ).…”

Section: Nlrp3 Inflammasome and Tlr2/4 Signaling Pathwaymentioning

confidence: 99%

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

Liu

Zhang

Liang

et al. 2022

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Schistosomiasis has been widely disseminated around the world, and poses a significant threat to human health. Schistosoma eggs and soluble egg antigen (SEA) mediated inflammatory responses promote the formation of egg granulomas and liver fibrosis. With continuous liver injuries and inflammatory stimulation, liver fibrosis can develop into liver cirrhosis and liver cancer. Therefore, anti-fibrotic therapy is crucial to increase the survival rate of patients. However, current research on antifibrotic treatments for schistosomiasis requires further exploration. In the complicated microenvironment of schistosome infections, it is important to understand the mechanism and pathology of schistosomiasis-associated liver fibrosis(SSLF). In this review, we discuss the role of SEA in inhibiting liver fibrosis, describe its mechanism, and comprehensively explore the role of host-derived and schistosome-derived microRNAs (miRNAs) in SSLF. Inflammasomes and cytokines are significant factors in promoting SSLF, and we discuss the mechanisms of some critical inflammatory signals and pro-fibrotic cytokines. Natural killer(NK) cells and Natural killer T(NKT) cells can inhibit SSLF but are rarely described, therefore, we highlight their significance. This summarizes and provides insights into the mechanisms of key molecules involved in SSLF development.

show abstract

Section: Nlrp3 Inflammasome and Tlr2/4 Signaling Pathwaymentioning

confidence: 99%

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

Liu

Zhang

Liang

et al. 2022

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…It has also been reported that Dectin-1 recruits RAC1 to produce ROS, which play an important role in the clearance of intracellular fungi [ 13 ]. In recent years, an increasing number of antifungal immune regulators have been identified, including PLC-γ2, PKC-δ, SHP-2, TAGAP, and EPHB2 [ 9 , 10 , 14 – 16 ]. In addition to the innate immune system, the adaptive immune system also plays an indispensable role in host defense against fungal infection.…”

Section: Introductionmentioning

confidence: 99%

DOCK2 regulates antifungal immunity by regulating RAC GTPase activity

Tan

et al. 2022

Cell Mol Immunol

Self Cite

View full text Add to dashboard Cite

Fungal infections cause ~1.5 million deaths each year worldwide, and the mortality rate of disseminated candidiasis currently exceeds that of breast cancer and malaria. The major reasons for the high mortality of candidiasis are the limited number of antifungal drugs and the emergence of drug-resistant species. Therefore, a better understanding of antifungal host defense mechanisms is crucial for the development of effective preventive and therapeutic strategies. Here, we report that DOCK2 (dedicator of cytokinesis 2) promotes indispensable antifungal innate immune signaling and proinflammatory gene expression in macrophages. DOCK2-deficient macrophages exhibit decreased RAC GTPase (Rac family small GTPase) activation and ROS (reactive oxygen species) production, which in turn attenuates the killing of intracellular fungi and the activation of downstream signaling pathways. Mechanistically, after fungal stimulation, activated SYK (spleen-associated tyrosine kinase) phosphorylates DOCK2 at tyrosine 985 and 1405, which promotes the recruitment and activation of RAC GTPases and then increases ROS production and downstream signaling activation. Importantly, nanoparticle-mediated delivery of in vitro transcribed (IVT) Rac1 mRNA promotes the activity of Rac1 and helps to eliminate fungal infection in vivo. Taken together, this study not only identifies a critical role of DOCK2 in antifungal immunity via regulation of RAC GTPase activity but also provides proof of concept for the treatment of invasive fungal infections by using IVT mRNA.

show abstract

“…However, excessive inflammation results in renal immunopathology during candidiasis suggesting that other mechanisms or RCDs fine-tune immunopathology and fungal control. Emerging data from various studies indicate an essential function of non-classical β-glucan recognition during fungal infections [33][34][35][36][37][38] . We recently found that EphA2 acts as a β-glucan receptor in the oral cavity that triggers the production of pro-inflammatory mediators via STAT3 and MAPK on oral epithelial cells, while EphA2 induces priming of neutrophil p47 phox to increase intracellular reactive oxygen species (ROS) production to enhance killing of opsonized C. albicans yeast 33,34 .…”

Section: Introductionmentioning

confidence: 99%

IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

Millet

Solis

Aquilar

et al. 2021

Preprint

View full text Add to dashboard Cite

During infection the host relies on pattern-recognition receptors to sense invading fungal pathogens to launch immune defense mechanisms. While fungal recognition and immune effector responses are organ and cell type specific, during disseminated candidiasis myeloid cells exacerbate collateral tissue damage. However, the complex interplay between protective antifungal immunity and immunopathology remains incompletely understood. The β-glucan receptor ephrin type-A 2 receptor (EphA2) is required to initiate mucosal inflammatory responses during oral Candida infection. Here we report that Epha2 promotes renal immunopathology during disseminated candidiasis. EphA2 deficiency leads to reduced renal inflammation and injury. Comprehensive analyses reveal that EphA2 limits IL-23 secretion in dendritic cells, while IL-23 signaling prevents ferroptotic myeloid cell death during infection. Further, ferroptosis aggravates inflammation during infection, while at the same time reducing the fungal killing capacity of macrophages. Thus, we identify ferroptotic cell death as a critical pathway of Candida-mediated renal immunopathology that opens a new avenue to tackle Candida infection and inflammation.

show abstract

Cutting Edge: EPHB2 Is a Coreceptor for Fungal Recognition and Phosphorylation of Syk in the Dectin-1 Signaling Pathway

Cited by 8 publications

References 20 publications

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

DOCK2 regulates antifungal immunity by regulating RAC GTPase activity

IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

Contact Info

Product

Resources

About