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Updated: Jun 1, 2026
Simultaneous Study of the Recruitment of Monocyte Subpopulations Under Flow In Vitro
Published on: November 26, 2018
Adam17-dependent shedding limits early neutrophil influx but does not alter early monocyte recruitment to
Jingjing Tang1, Alexander Zarbock, Ivan Gomez
1Department of Pathology, University of Washington, Seattle, WA 98104, USA.
Abstract:
TNF-α-converting enzyme (TACE, herein denoted as Adam17) proteolytically sheds several cell-surface inflammatory proteins, but the physiologic importance of the cleavage of these substrates from leukocyte subsets during inflammation is incompletely understood. In this study, we show that Adam17-null neutrophils have a 2-fold advantage in their initial recruitment during thioglycollate-induced peritonitis, and they roll slower and adhere more readily in the cremaster model than wild-type neutrophils. Although CD44 and ICAM-1 are both in vitro substrates of Adam17, their surface levels are not altered on Adam17-null neutrophils. In contrast, L-selectin levels are elevated up to 10-fold in Adam17-null circulating neutrophils, and their accelerated peritoneal influx, slower rolling, and increased adhesion in the cremaster muscle are dependent on L-selectin. Analysis of mixed chimeras shows that enhanced L-selectin levels and accelerated influx were both cell-intrinsic properties of neutrophils lacking Adam17. In contrast, Adam17-null monocytes display no acceleration of infiltration into the peritoneum in spite of elevated L-selectin surface levels, and their peritoneal influx was independent of L-selectin. Therefore, our data demonstrate substrate and myeloid cell-type specificity of Adam17-mediated cleavage of its substrates, and show that neutrophils and monocytes use distinct mechanisms for infiltration of tissues.
Insights
Mice lacking TNF-α-converting enzyme (TACE, Adam17) show enhanced neutrophil recruitment due to elevated L-selectin. This study reveals cell-type specific roles for Adam17 in leukocyte infiltration during inflammation.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- TNF-α-converting enzyme (TACE, Adam17) cleaves cell-surface proteins, but its role in leukocyte recruitment during inflammation is unclear.
- Understanding Adam17's function in substrate shedding from immune cells is crucial for inflammatory disease research.
Purpose of the Study:
- To investigate the physiological importance of Adam17 in leukocyte subset infiltration during inflammation.
- To determine the role of Adam17 in the shedding of inflammatory proteins and its impact on neutrophil and monocyte recruitment.
Main Methods:
- Utilized Adam17-null mice and wild-type controls.
- Examined neutrophil and monocyte recruitment in thioglycollate-induced peritonitis and cremaster muscle models.
- Analyzed surface levels of key proteins like L-selectin, CD44, and ICAM-1.
- Employed mixed chimera analysis to assess cell-intrinsic properties.
Main Results:
- Adam17-null neutrophils exhibited a 2-fold increase in recruitment, slower rolling, and enhanced adhesion, dependent on L-selectin.
- Elevated L-selectin levels (up to 10-fold) were observed on Adam17-null neutrophils.
- Adam17-null monocytes showed no accelerated peritoneal infiltration, despite elevated L-selectin, and their recruitment was L-selectin-independent.
- Cell-intrinsic properties of neutrophils lacking Adam17 accounted for enhanced L-selectin levels and accelerated influx.
Conclusions:
- Adam17 exhibits substrate and myeloid cell-type specificity in cleaving its substrates.
- Neutrophils and monocytes utilize distinct mechanisms for tissue infiltration, modulated by Adam17.
- L-selectin plays a critical, cell-intrinsic role in Adam17-null neutrophil recruitment.
