Ectopic Expression of C-Type Lectin Mincle Renders Mice Susceptible to Staphylococcal Pneumonia
Femke D Hollwedel1, Regina Maus1, Jennifer Stolper1
1Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany.
Abstract:
Staphylococcus aureus is a prevalent pathogen in pneumonia and harbors glycolipids, which may serve as molecular patterns in Mincle (macrophage-inducible C-type lectin)-dependent pathogen recognition. We examined the role of Mincle in lung defense against S aureus in wild-type (WT), Mincle knockout (KO), and Mincle transgenic (tg) mice. Two glycolipids, glucosyl-diacylglycerol (Glc-DAG) and diglucosyl-diacylglycerol (Glc2-DAG), were purified, of which only Glc-DAG triggered Mincle reporter cell activation and professional phagocyte responses. Proteomic profiling revealed that Glc2-DAG blocked Glc-DAG-induced cytokine responses, thereby acting as inhibitor of Glc-DAG/Mincle signaling. WT mice responded to S aureus with a similar lung pathology as Mincle KO mice, most likely due to Glc2-DAG-dependent inhibition of Glc-DAG/Mincle signaling. In contrast, ectopic Mincle expression caused severe lung pathology in S aureus-infected mice, characterized by bacterial outgrowth and fatal pneumonia. Collectively, Glc2-DAG inhibits Glc-DAG/Mincle-dependent responses in WT mice, whereas sustained Mincle expression overrides Glc2-DAG-mediated inhibitory effects, conferring increased host susceptibility to S aureus.
Insights
Staphylococcus aureus pneumonia involves Mincle (macrophage-inducible C-type lectin) signaling. A glycolipid inhibitor (Glc2-DAG) blocks Mincle responses in wild-type mice, but high Mincle expression worsens S. aureus lung infection.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Staphylococcus aureus is a common cause of pneumonia.
- Glycolipids from S. aureus may be recognized by Mincle (macrophage-inducible C-type lectin).
- Mincle plays a role in innate immune responses to pathogens.
Purpose of the Study:
- To investigate the role of Mincle in host defense against S. aureus lung infection.
- To identify specific glycolipids involved in Mincle-dependent recognition of S. aureus.
- To elucidate the mechanism of Mincle-mediated immune responses during S. aureus pneumonia.
Main Methods:
- Comparative analysis of lung pathology in wild-type, Mincle knockout, and Mincle transgenic mice infected with S. aureus.
- Purification and characterization of glycolipids from S. aureus.
- Assessment of Mincle reporter cell activation and phagocyte responses to purified glycolipids.
- Proteomic profiling to analyze cytokine responses and signaling pathways.
Main Results:
- Only glucosyl-diacylglycerol (Glc-DAG) activated Mincle and phagocyte responses.
- Diglucosyl-diacylglycerol (Glc2-DAG) inhibited Glc-DAG-induced Mincle signaling and cytokine production.
- Wild-type mice showed similar lung pathology to Mincle knockout mice, suggesting Glc2-DAG-mediated inhibition.
- Transgenic mice with high Mincle expression exhibited severe pneumonia and bacterial outgrowth upon S. aureus infection.
Conclusions:
- Glc2-DAG acts as an endogenous inhibitor of Glc-DAG/Mincle signaling in S. aureus pneumonia.
- Mincle-dependent immune responses are crucial for controlling S. aureus lung infection.
- Sustained Mincle expression can overcome Glc2-DAG inhibition, leading to increased susceptibility to S. aureus.
