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Human neutrophil-derived CAP37 inhibits lipopolysaccharide-induced activation in murine peritoneal macrophages
Herbert Bosshart1, Michael Heinzelmann
1Department of Surgery, Zurich University Hospital, Sternwartstrasse 14, CH-8091 Zurich, Switzerland. herbert.bosshart@usz.ch
Abstract:
Human cationic antimicrobial protein, CAP37, is released from neutrophil granules during infection. CAP37 attracts monocytes, binds Gram-negative endotoxin (lipopolysaccharide, LPS), is bactericidal for a range of Gram-negative bacteria, and reduces mortality in murine polymicrobial sepsis. Here, we report that recombinant CAP37 specifically targets murine peritoneal macrophages. Under steady-state conditions, the bulk of cell-associated CAP37 was localized at the plasma membrane. However, a fraction of CAP37 gained access to the endocytic system, but did not accumulate in recycling endosomes or in the trans-Golgi network (TGN). Instead, CAP37 was internalized by fluid phase endocytosis and accumulated in a prelysosomal compartment. Macrophages that were preexposed to CAP37 exhibited diminished LPS responsiveness, as determined by analysis of c-Jun phosphorylation. Further examination showed that pretreatment with CAP37 reduced the ability of macrophages to bind LPS. Taken together, these observations demonstrate that prolonged exposure to CAP37 desensitizes macrophages to LPS and suggest that this protein plays a novel anti-inflammatory role in polymicrobial sepsis.
Insights
Human cationic antimicrobial protein (CAP37) targets macrophages, reducing their response to lipopolysaccharide (LPS). This suggests CAP37 plays an anti-inflammatory role in sepsis by desensitizing immune cells.
Area of Science:
- Immunology
- Cell Biology
Background:
- Human cationic antimicrobial protein (CAP37) is released by neutrophils during infection.
- CAP37 exhibits antimicrobial properties, attracts monocytes, and binds lipopolysaccharide (LPS).
Purpose of the Study:
- To investigate the interaction of recombinant CAP37 with murine peritoneal macrophages.
- To determine the functional consequences of CAP37 exposure on macrophage LPS responsiveness.
Main Methods:
- Tracking of fluorescently labeled CAP37 in macrophages using microscopy.
- Assessment of macrophage LPS responsiveness via c-Jun phosphorylation analysis.
- Evaluation of macrophage LPS binding capacity after CAP37 pretreatment.
Main Results:
- Recombinant CAP37 was specifically targeted by murine peritoneal macrophages.
- CAP37 was internalized via fluid phase endocytosis and localized to a prelysosomal compartment.
- Macrophages pre-exposed to CAP37 showed reduced LPS responsiveness and decreased LPS binding.
Conclusions:
- Prolonged exposure to CAP37 desensitizes macrophages to LPS.
- CAP37 may exert an anti-inflammatory effect in polymicrobial sepsis by modulating macrophage responses.
