Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway.
Justin S A Perry1,2,3, Sho Morioka1,2,4, Christopher B Medina1,2
1The Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA.
Nature Cell Biology
|December 4, 2019
Summary
A novel chloride-sensing pathway regulates how phagocytes clear apoptotic cells. This pathway influences phagocyte appetite and inflammatory responses, revealing new mechanisms in efferocytosis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Apoptotic cell clearance (efferocytosis) by phagocytes normally induces an anti-inflammatory response.
- The precise molecular mechanisms governing this anti-inflammatory outcome are not fully understood.
Purpose of the Study:
- To identify novel signaling pathways that regulate phagocyte efferocytosis and the associated inflammatory response.
- To elucidate the role of chloride ion sensing in modulating phagocyte function during efferocytosis.
Main Methods:
- Investigated transcriptional changes in phagocytes during efferocytosis, focusing on solute carrier (SLC) proteins.
- Utilized genetic manipulation (knockdown/deficiency) of SLC12A2 and SLC12A4 to assess their impact on efferocytosis.
- Examined the role of upstream chloride-sensing kinases (WNK1, OSR1, SPAK) in the efferocytosis pathway.
Main Results:
- Efferocytosis induced the expression of SLC12A2 and SLC12A4.
- Loss of SLC12A2 enhanced apoptotic cell uptake, while loss of SLC12A4 impaired it.
- Disruption of the WNK1-OSR1-SPAK-SLC12A2/SLC12A4 pathway shifted phagocytes from an anti-inflammatory to a pro-inflammatory and oxidative stress gene program.
Conclusions:
- A chloride-sensing pathway involving WNK1, OSR1, SPAK, SLC12A2, and SLC12A4 regulates phagocyte efferocytosis.
- Chloride flux through these transporters is critical for phagocytes to interpret engulfed apoptotic cells correctly, maintaining an anti-inflammatory state.
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