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Macrophage Cholesterol Depletion and Its Effect on the Phagocytosis of Cryptococcus neoformans
Published on: December 19, 2014
Limited Role of Mincle in the Host Defense against Infection with Cryptococcus deneoformans
Yuki Sato1, Ko Sato2, Hideki Yamamoto1
1Department of Medical Microbiology, Mycology, and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Abstract:
Cryptococcus deneoformans is an opportunistic fungal pathogen that frequently causes fatal meningoencephalitis in patients with impaired cell-mediated immune responses such as AIDS. Caspase-associated recruitment domain 9 (CARD9) plays a critical role in the host defense against cryptococcal infection, suggesting the involvement of one or more C-type lectin receptors (CLRs). In the present study, we analyzed the role of macrophage-inducible C-type lectin (Mincle), one of the CLRs, in the host defense against C. deneoformans infection. Mincle expression in the lungs of wild-type (WT) mice was increased in the early stage of cryptococcal infection in a CARD9-dependent manner. In Mincle gene-disrupted (Mincle KO) mice, the clearance of this fungus, pathological findings, Th1/Th2 response, and antimicrobial peptide production in the infected lungs were nearly comparable to those in WT mice. However, the production of interleukin-22 (IL-22), tumor necrosis factor alpha (TNF-α), and IL-6 and the expression of AhR were significantly decreased in the lungs of Mincle KO mice compared to those of WT mice. In in vitro experiments, TNF-α production by bone marrow-derived dendritic cells was significantly decreased in Mincle KO mice. In addition, the disrupted lysates of C. deneoformans, but not those of whole yeast cells, activated Mincle-triggered signaling in an assay with a nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cells expressing this receptor. These results suggest that Mincle may be involved in the production of Th22-related cytokines at the early stage of cryptococcal infection, although its role may be limited in the host defense against infection with C. deneoformans.
Insights
Macrophage-inducible C-type lectin (Mincle) plays a limited role in host defense against Cryptococcus deneoformans infection. While Mincle influences cytokine production like IL-22, its absence did not significantly alter fungal clearance or pathology in mice.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Cryptococcus deneoformans is an opportunistic fungal pathogen causing fatal meningoencephalitis, particularly in immunocompromised individuals.
- Caspase-associated recruitment domain 9 (CARD9) is crucial for host defense against C. deneoformans, implying involvement of C-type lectin receptors (CLRs).
- Macrophage-inducible C-type lectin (Mincle) is a CLR whose role in cryptococcal infection warrants investigation.
Purpose of the Study:
- To investigate the role of Mincle in host defense against C. deneoformans infection.
- To determine Mincle's involvement in immune responses during cryptococcal infection in mice.
Main Methods:
- Compared Mincle gene-disrupted (Mincle KO) mice with wild-type (WT) mice during C. deneoformans infection.
- Assessed fungal clearance, lung pathology, Th1/Th2 responses, cytokine production (IL-22, TNF-α, IL-6), and Aryl hydrocarbon receptor (AhR) expression.
- Utilized in vitro assays with bone marrow-derived dendritic cells and NFAT-GFP reporter cells to study Mincle signaling activation by C. deneoformans components.
Main Results:
- Mincle expression increased in WT mice lungs during early infection, dependent on CARD9.
- Mincle KO mice showed comparable fungal clearance, pathology, and Th1/Th2 responses to WT mice.
- Mincle deficiency led to significantly decreased production of IL-22, TNF-α, IL-6, and reduced AhR expression in infected lungs.
- In vitro, Mincle deficiency reduced TNF-α production by dendritic cells and Mincle-triggered signaling by C. deneoformans lysates.
Conclusions:
- Mincle appears to contribute to the production of Th22-related cytokines during the early stages of C. deneoformans infection.
- The role of Mincle in overall host defense against C. deneoformans infection is limited, as its absence did not severely impair fungal clearance or pathology.
- Mincle signaling is activated by disrupted C. deneoformans cells, suggesting a specific recognition mechanism.
