Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway
UID: 11000
- Description
- Summary from GEO:
"Phagocytes in different tissues recognize and remove apoptotic cells via the process of efferocytosis. Although it is well-established that efferocytosis elicits an anti-inflammatory response by phagocytes, the molecules and mechanisms that enforce this response in phagocytes are still being defined. In attempting to decipher gene programs induced after a phagocyte ingests a dying cell, we uncovered a chloride-sensing signaling pathway that controls both the ‘appetite’ of a phagocyte and how a phagocyte responds after corpse uptake. First, we noted that within phagocytes that have ingested a corpse, the solute carrier 12 (SLC12) family members SLC12A2 and SLC12A4 are actively modulated. Interfering with SLC12A2, either genetically or pharmacologically, led to significantly enhanced corpse uptake per phagocyte, while loss of SLC12A4 inhibited corpse uptake. Interestingly, when phagocytes with disrupted SLC12A2 engulfed apoptotic corpses, the typical homeostatic efferocytosis signature was perturbed, characterized by loss of the canonical anti-inflammatory program and replaced by pro-inflammatory and oxidative stress-associated gene programs. In further mechanistic studies, we observed efferocytosis was also regulated by the chloride-sensing pathway upstream of SLC12A2, including the kinases WNK1-OSR1-SPAK, and this involved chloride entry/exit across the plasma membrane of phagocytes during corpse engulfment. We also show that the ‘switch’ to pro-inflammatory sensing of apoptotic cells is specifically due to disruption of the chloride-sensing pathway and not due to corpse overload or poor degradation, and that the pro-inflammatory gene signature can be reversed using a chloride ionophore. Collectively, these data identify the WNK1-OSR1-SPAK-SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes as key modifiers of how a phagocyte interprets an engulfed apoptotic corpse."
Overall design from GEO:
"The first experiment consisted of four conditions: Phagocytes (LR73 cells) alone, treated with cytochalasin-D, co-cultured with apoptotic Jurkat lymphoma cells, or treated with cytochalasin-D and co-cultured with apoptotic Jurkat lymphoma cells. The second experiment consisted of two conditions, wildtype or Slc12a2-deficient LR73 phagocytes. Phagocytes were co-cultured with apoptotic Jurkat cellsfor 2h, then actively engulfing phagocytes (i.e. CypHer5E+) were FACS-sorted prior to RNA isolation. All conditions consisted of four biological replicates."
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Access via GEO
Accession #: GSE131860Access via BioProject
Accession #: PRJNA545135Access via SRA
Accession #: SRP199669 - Access Restrictions
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Free to All
- Access Instructions
- The NCBI Gene Expression Omnibus, BioProject, and SRA databases provide open access to these files.
- Associated Publications
- Equipment Used
- Dataset Format(s)
- TXT
- Dataset Size
- 4.4 MB (2 TXT files)
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