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BLNK negatively regulates C-type lectin receptor-mediated antifungal immunity through inhibiting macrophage migration

ABSTRACT: BLNK negatively regulates C-type lectin receptor-mediated antifungal immunity through inhibiting macrophage migration

PROVIDER: PRJNA1035062 | ENA |

REPOSITORIES: ENA

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BLNK negatively regulates C-type lectin receptor-mediated antifungal immunity through inhibiting macrophage migration

Project description:B cell linker protein (BLNK) is a pivotal adaptor protein that interfaces the B cell receptor (BCR)-associated spleen tyrosine kinase (Syk) to regulate B cell function and development. However, it is still not well understood whether BLNK is involved in Syk-coupled C-type lectin receptor (CLR) signaling in myeloid cells, particularly in the context of antifungal immunity. Here, we show that stimulation with fungi-derived β-glucans or α-mannans induced the phosphorylation of BLNK in macrophages, which was significantly impaired due to the deficiency of CLRs including Dectin-1 and Dectin-2, as well as their downstream mediators Syk and Fc-receptor gamma-chain (FcRγ). Furthermore, BLNK is induced to be interacted with casitas B-lineage lymphoma (c-Cbl), which is completely dependent on the engagement of Dectin-1 and Dectin-2. Notably, BLNK deficiency facilitates CLR-mediated recruitment of c-Cbl/phosphatidylinositol 3-kinase (PI3K) complex to F-actin cytoskeleton, thereby promoting macrophage migration. Consequently, mice with monocyte-specific deficiency of BLNK are highly resistant to the infection with Candida albicans, a major human fungal pathogen, through increasing the infiltration of Ly6C+macrophages into kidneys. Together, our data indicate that BLNK functions downstream of Syk-coupled CLRs to negatively regulate antifungal immunity against C. albicans infection. These findings unravel a previously unidentified role of BLNK that negatively regulates macrophage migration through inhibiting CLR-mediated recruitment of c-Cbl/PI3K complex to the cytoskeleton.

2023-11-07 | GSE246891 | GEO

N4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization

Project description:N4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization

| PRJNA698568 | ENA

Epithelial miR-215 negatively modulates Th17-dominant inflammation by inhibiting CXCL12 production in the small intestine

Project description:Epithelial miR-215 negatively modulates Th17-dominant inflammation by inhibiting CXCL12 production in the small intestine

| PRJNA775624 | ENA

Epithelial miR-215 negatively modulates Th17-dominant inflammation by inhibiting CXCL12 production in the small intestine

Project description:MicroRNAs are a class of non-coding short-chained RNAs that control cellular functions by downregulating their target genes. Recent research indicates that microRNAs play a role in the maintenance of gut homeostasis. miR-215 was found to be highly expressed in epithelial cells of the small intestine; however, the involvement of miR-215 in gut immunity remains unknown. Here, we show that miR-215 negatively regulates inflammation in the small intestine by inhibiting CXCL12 production. Mice lacking miR-215 showed high susceptibility to inflammation induced by indomethacin, accompanied by an increased number of Th17 cells in the lamina propria of the small intestine. Our findings support a promising perspective of targeting miR-215 to treat inflammatory conditions in the small intestine.

2022-01-27 | GSE186708 | GEO

PD-L1 negatively regulates antifungal immunity by inhibiting neutrophil release from bone marrow.

Project description:Programmed death ligand 1 (PD-L1) has been shown to be inducibly expressed on neutrophils to suppress host immunity during polymicrobial sepsis, virus and parasite infections. However, the role of PD-L1 on neutrophil-mediated antifungal immunity remains wholly unknown. Here, we show that the expression of PD-L1 on murine and human neutrophils was upregulated upon the engagement of C-type lectin receptor Dectin-1 with its ligand β-glucans, exposed on fungal pathogen Candida albicans yeast. Moreover, β-glucan stimulation induced PD-L1 translocation into nucleus to regulate the production of chemokines CXCL1 and CXCL2, which control neutrophil mobilization. Importantly, C. albicans infection-induced expression of PD-L1 leads to neutrophil accumulation in bone marrow, through mediating their autocrine secretion of CXCL1/2. Furthermore, neutrophil-specific deficiency of PD-L1 impaired CXCL1/2 secretion, which promoted neutrophil migration from bone marrow into the peripheral circulation, thereby conferring host resistance to C. albicans infection. Finally, either PD-L1 blockade or pharmacological inhibition of PD-L1 expression significantly increased neutrophil release from bone marrow to enhance host antifungal immunity. Our data together indicate that activation of Dectin-1/PD-L1 cascade by β-glucans inhibits neutrophil release from bone marrow reserve, contributing to the negative regulation of antifungal innate immunity, which functions as a potent immunotherapeutic target against life-threatening fungi infections.

| S-EPMC9652346 | biostudies-literature

Evaluating the mode of Antifungal action of Heat-Stable Antifungal Factor (HSAF) in Neurospora crassa

Project description:Heat-stable antifungal factor (HSAF) isolated from Lysobacter enzymogenes has shown a broad-spectrum of antifungal activities. However, little is known about its mode of action. In this study, we used the model filamentous fungus Neurospora crassa to investigate the antifungal mechanism of HSAF. We first used HSAF to treat N. crassa strain for different time points. Spore germination, growth phenotype and differential gene expression analysis were conducted by utilizing global transcriptional profiling combined with genetic and physiological analyses. Our data showed that HSAF could significantly inhibit the germination and aerial hyphae growth of N.crassa. RNA-seq analysis showed a group of genes associated with cell wall formation and remodeling were highly activated. Screening of N. crassa gene deletion mutants combined with scanning electron microscopic observation revealed 3 fungal cell wall integrity related genes played important role in the interaction between N. crassa and L. enzymogens. In addition, WGCNA analysis, accompany with confocal microscopy observation revealed that HSAF could trigger autophagy mediated degradation and eventually result in cell death in N. crassa. The findings of this work provided new insights into the interactions between the predatory Lysobacter and its fungal prey.

2022-01-28 | GSE195441 | GEO

Aspergillus fumigatus Af293 response to lactic acid bacteria antifungal activity

Project description:The effect of cell free supernatant from the antifungal strain Lactobacillus plantarum 16 on the growth of Aspergillus fumigatus Af293 was assessed. Transcriptome analysis of the genome was performed after ten minutes exposure to antifungal supernatant in order to determine the molecular targets involved in inhibtion.

2013-08-09 | E-MTAB-1701 | biostudies-arrayexpress

Antifungal agent tempol

Project description:Stable Redox-Cycling Nitroxide Tempol has Antifungal and Immune-modulatory Properties

| PRJEB31969 | ENA

Mus musculus

Project description:C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity

| PRJNA962091 | ENA

Tet2 negatively regulates memory fidelity

Project description:Tet2 negatively regulates memory fidelity

| PRJNA590200 | ENA