SHIP represses the generation of alternatively activated macrophages.
We recently reported that SHIP restrains LPS-induced classical (M1) activation of in vitro differentiated, bone marrow-derived macrophages (BMMPhis) and that SHIP upregulation is essential for endotoxin tolerance. Herein, we show that in vivo differentiated SHIP-/- peritoneal (PMPhis) and alveolar (AMPhis) macrophages, unlike their wild-type counterparts, are profoundly M2 skewed (alternatively activated), possessing constitutively high arginase I (ArgI) and Ym1 levels and impaired LPS-induced NO production. Consistent with this, SHIP-/- mice display M2-mediated lung pathology and enhanced tumor implant growth. Interestingly, BMMPhis from SHIP-/- mice do not display this M2 phenotype unless exposed to TGFbeta within normal mouse plasma (MP) during in vitro differentiation. Our results suggest that SHIP functions in vivo to repress M2 skewing and that macrophage polarization can occur during differentiation in response to TGFbeta if progenitors have elevated PIP3.
Rauh
Michael J
MJ
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
Ho
Victor
V
Pereira
Carla
C
Sham
Anita
A
Sly
Laura M
LM
Lam
Vivian
V
Huxham
Lynsey
L
Minchinton
Andrew I
AI
Mui
Alice
A
Krystal
Gerald
G
D000367:Age Factors; D000818:Animals; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D001120:Arginine; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases