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Phospholipase C?2 (PLC?2) is key component in Dectin-2 signaling pathway, mediating anti-fungal innate immune responses.

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 C?2 (PLC?2) 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 PLC?2 functions downstream of Dectin-2 in response to the stimulation by the hyphal form of Candida albicans, an opportunistic pathogenic fungus. Using PLC?2- and PLC?1-deficient macrophages, we found that the lack of PLC?2, but not PLC?1, impairs cytokine production in response to infection with C. albicans. PLC?2 deficiency results in the defective activation of NF-?B and MAPK and a significantly reduced production of reactive oxygen species following fungal challenge. In addition, 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.

SUBMITTER: Gorjestani S

PROVIDER: S-EPMC3243564 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Phospholipase Cγ2 (PLCγ2) is key component in Dectin-2 signaling pathway, mediating anti-fungal innate immune responses.

Gorjestani Sara S Yu Mei M Tang Bing B Zhang Dekai D Wang Demin D Lin Xin X

The Journal of biological chemistry 20111031 51

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 characteri ...[more]

PMID: 22041900

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Project description:BackgroundAutoinflammatory phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) is a rare autoinflammatory disease caused by gain-of-function mutations in the PLCG2 gene. Here we report a rare case of APLAID patient carrying a novel heterozygous missense PLCG2 I169V mutation with gangrenous pyoderma and concomitant high serum immunoglobulin (Ig) E level.MethodsThe patient was diagnosed as APLAID and has been treated in our department. His phenotype and genotype were carefully documented and studied. We also conducted a comprehensive literature review on APLAID.ResultsA 23-year-old Chinese Han man presented with recurrent fever for 18 years and vesiculopustular rashes for 9 years, along with chronic bronchitis, leukocytosis, increased C-reactive protein, immunodeficiency and high serum IgE. Skin biopsy showed chronic inflammatory cells infiltration. A paternal heterozygous missense variant in exon 6 of the PLCG2 gene p. I169V was identified. His vesiculopustular and IgE level responded to medium dose corticosteroids. After withdrawal of steroids, he developed severe arthritis and a large deteriorating ulceration resembling pyoderma gangrenosum on the left knee. Large dose corticosteroids were suboptimal. Then he received adalimumab with satisfactory response for arthritis and skin lesion. But he got an immunodeficiency-associated lymphoproliferative disorder 2 months later. Through literature review, there were a total of 10 APLAID patients reported by six English-language publications. Vesiculopustular rashes, sinopulmonary infection and immunodeficiency were the most frequent symptoms of APLAID patients. Glucocorticoids, intravenous immunoglobulin and biologics were clinically used to treat APLAID but none of these patients had a complete recovery.ConclusionsThe rarity and diversity of APLAID make it difficult to be diagnosed. Our study reported the first case of APLAID with gangrenous pyoderma and concomitant high IgE carrying a novel PLCG2 mutation, which may expand the clinical phenotype and genotype of APLAID.

Project description:The scavenger receptor MARCO is expressed in several subsets of naive tissue-resident macrophages and has been shown to participate in the recognition of various bacterial pathogens. However, the role of MARCO in antiviral defense is largely unexplored. Here, we investigated whether MARCO might be involved in the innate sensing of infection with adenovirus and recombinant adenoviral vectors by macrophages, which elicit vigorous immune responses in vivo Using cells derived from mice, we show that adenovirus infection is significantly more efficient in MARCO-positive alveolar macrophages (AMs) and in AM-like primary macrophage lines (Max Planck Institute cells) than in MARCO-negative bone marrow-derived macrophages. Using antibodies blocking ligand binding to MARCO, as well as gene-deficient and MARCO-transfected cells, we show that MARCO mediates the rapid adenovirus transduction of macrophages. By enhancing adenovirus infection, MARCO contributes to efficient innate virus recognition through the cytoplasmic DNA sensor cGAS. This leads to strong proinflammatory responses, including the production of interleukin-6 (IL-6), alpha/beta interferon, and mature IL-1α. These findings contribute to the understanding of viral pathogenesis in macrophages and may open new possibilities for the development of tools to influence the outcome of infection with adenovirus or adenovirus vectors.IMPORTANCE Macrophages play crucial roles in inflammation and defense against infection. Several macrophage subtypes have been identified with differing abilities to respond to infection with both natural adenoviruses and recombinant adenoviral vectors. Adenoviruses are important respiratory pathogens that elicit vigorous innate responses in vitro and in vivo The cell surface receptors mediating macrophage type-specific adenovirus sensing are largely unknown. The scavenger receptor MARCO is expressed on some subsets of naive tissue-resident macrophages, including lung alveolar macrophages. Its role in antiviral macrophage responses is largely unexplored. Here, we studied whether the differential expression of MARCO might contribute to the various susceptibilities of macrophage subtypes to adenovirus. We demonstrate that MARCO significantly enhances adenovirus infection and innate responses in macrophages. These results help to understand adenoviral pathogenesis and may open new possibilities to influence the outcome of infection with adenoviruses or adenovirus vectors.

Dataset Information

Phospholipase C?2 (PLC?2) is key component in Dectin-2 signaling pathway, mediating anti-fungal innate immune responses.

Publications

Phospholipase Cγ2 (PLCγ2) is key component in Dectin-2 signaling pathway, mediating anti-fungal innate immune responses.

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