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Mincle activation enhances neutrophil migration and resistance to polymicrobial septic peritonitis
Wook-Bin Lee1, Ji-Jing Yan2, Ji-Seon Kang1
1Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Abstract:
Sepsis is a systemic inflammatory response to bacterial infection. The therapeutic options for treating sepsis are limited. Impaired neutrophil recruitment into the infection site is directly associated with severe sepsis, but the precise mechanism is unclear. Here, we show that Mincle plays a key role in neutrophil migration and resistance during polymicrobial sepsis. Mincle-deficient mice exhibited lower survival rates in experimental sepsis from cecal ligation and puncture and Escherichia coli-induced peritonitis. Mincle deficiency led to higher serum inflammatory cytokine levels and reduced bacterial clearance and neutrophil recruitment. Transcriptome analyses revealed that trehalose dimycolate, a Mincle ligand, reduced the expression of G protein-coupled receptor kinase 2 (GRK2) in neutrophils. Indeed, GRK2 expression was upregulated, but surface expression of the chemokine receptor CXCR2 was downregulated in blood neutrophils from Mincle-deficient mice with septic injury. Moreover, CXCL2-mediated adhesion, chemotactic responses, and F-actin polymerization were reduced in Mincle-deficient neutrophils. Finally, we found that fewer Mincle-deficient neutrophils infiltrated from the blood circulation into the peritoneal fluid in bacterial septic peritonitis compared with wild-type cells. Thus, our results indicate that Mincle plays an important role in neutrophil infiltration and suggest that Mincle signaling may provide a therapeutic target for treating sepsis.
Insights
Mincle is crucial for neutrophil migration and survival in sepsis. Mincle deficiency impairs neutrophil function, leading to increased mortality in experimental sepsis models.
Area of Science:
- Immunology
- Microbiology
- Pathophysiology
Background:
- Sepsis is a life-threatening systemic inflammatory response to infection.
- Limited therapeutic options exist for sepsis treatment.
- Impaired neutrophil recruitment is linked to severe sepsis, but mechanisms are unclear.
Purpose of the Study:
- To investigate the role of Mincle in neutrophil migration and resistance during polymicrobial sepsis.
- To elucidate the molecular mechanisms underlying Mincle's function in sepsis.
Main Methods:
- Utilized Mincle-deficient mice in experimental sepsis models (cecal ligation and puncture, E. coli peritonitis).
- Assessed survival rates, serum cytokine levels, bacterial clearance, and neutrophil recruitment.
- Performed transcriptome analysis to identify Mincle ligand effects on neutrophil gene expression.
- Quantified neutrophil infiltration and chemokine receptor expression (CXCR2).
Main Results:
- Mincle-deficient mice showed reduced survival rates and impaired bacterial clearance in sepsis models.
- Mincle deficiency led to elevated serum inflammatory cytokines and decreased neutrophil recruitment to infection sites.
- Trehalose dimycolate, a Mincle ligand, downregulated GRK2 expression in neutrophils.
- Mincle-deficient neutrophils exhibited upregulated GRK2, downregulated CXCR2, and reduced CXCL2-mediated functions.
Conclusions:
- Mincle plays a critical role in neutrophil infiltration and host resistance during polymicrobial sepsis.
- Mincle signaling influences neutrophil chemokine receptor expression and function.
- Targeting Mincle signaling presents a potential therapeutic strategy for sepsis treatment.
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