Receptor-interacting protein-2 deficiency delays macrophage migration and increases intracellular infection during peritoneal dialysis-associated peritonitis.
BACKGROUND
Early upregulation of receptor-interacting protein-2 (RIP2) expression during peritoneal dialysis (PD)-associated peritonitis correlates with a favorable clinical outcome, while failure to upregulate RIP2 correlates with a protracted course. We noticed that patients who do not upregulate RIP2 during PD-associated peritonitis have more peritoneal macrophages during the early phase of infection.


METHODS
To study the mechanism behind this observation, we examined the role of RIP2 in the immune response to bacterial challenge in a mouse model of acute peritonitis. We injected RIP2(+/+) and RIP2(-/-) mice intraperitoneally with a Staphylococcus epidermidis cell free-preparation, and peritoneal cells were isolated 3, 6 and 24 h after challenge.


RESULTS
Surprisingly, RIP2(-/-) mice had a comparable influx of inflammatory leukocytes, but had a significantly higher number of peritoneal macrophages at 3 h, indicating delayed emigration of these cells. No significant differences were seen at later times suggesting that migration was delayed but not inhibited. In addition, RIP2(-/-) macrophages were more permissive to intracellular infection by Staphylococcus aureus, indicating that, in the absence of RIP2, resident peritoneal macrophages could become reservoirs of bacteria.


CONCLUSIONS
These findings provide a mechanism for the observation that upregulation of RIP2 expression is required for rapid resolution of peritonitis, by decreasing intracellular infection and by regulating the migration of antigen-presenting cells in the early stages of an inflammatory response.
McCully
Michelle L
ML
FOCIS Centre for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
Fairhead
Todd
T
Colmont
Chantal S
CS
Beasley
Federico C
FC
Heinrichs
David E
DE
Blake
Peter G
PG
Topley
Nicholas
N
Madrenas
Joaquín
J
D000818:Animals; D002465:Cell Movement; D002474:Cell-Free System; D006801:Humans; D007239:Infections / Q000378:metabolism; D007249:Inflammation; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D010538:Peritonitis / Q000150:complications*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000172:deficiency*; D013212:Staphylococcus epidermidis / Q000378:metabolism; D013997:Time Factors
D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2