GM-CSF Promotes Macrophage Alternative Activation after Renal Ischemia/Reperfusion Injury.
After kidney ischemia/reperfusion (I/R) injury, monocytes home to the kidney and differentiate into activated macrophages. Whereas proinflammatory macrophages contribute to the initial kidney damage, an alternatively activated phenotype can promote normal renal repair. The microenvironment of the kidney during the repair phase mediates the transition of macrophage activation from a proinflammatory to a reparative phenotype. In this study, we show that macrophages isolated from murine kidneys during the tubular repair phase after I/R exhibit an alternative activation gene profile that differs from the canonical alternative activation induced by IL-4-stimulated STAT6 signaling. This unique activation profile can be reproduced in vitro by stimulation of bone marrow-derived macrophages with conditioned media from serum-starved mouse proximal tubule cells. Secreted tubular factors were found to activate macrophage STAT3 and STAT5 but not STAT6, leading to induction of the unique alternative activation pattern. Using STAT3-deficient bone marrow-derived macrophages and pharmacologic inhibition of STAT5, we found that tubular cell-mediated macrophage alternative activation is regulated by STAT5 activation. Both in vitro and after renal I/R, tubular cells expressed GM-CSF, a known STAT5 activator, and this pathway was required for in vitro alternative activation of macrophages by tubular cells. Furthermore, administration of a neutralizing antibody against GM-CSF after renal I/R attenuated kidney macrophage alternative activation and suppressed tubular proliferation. Taken together, these data show that tubular cells can instruct macrophage activation by secreting GM-CSF, leading to a unique macrophage reparative phenotype that supports tubular proliferation after sterile ischemic injury.
Section of Nephrology, Department of Medicine, sarah.huen@yale.edu.
Sarah C
SC
Huen
Yale Cancer Center, and.
Larry
L
Huynh
Section of Nephrology, Department of Medicine.
Arnaud
A
Marlier
Section of Nephrology, Department of Medicine.
Yashang
Y
Lee
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Gilbert W
GW
Moeckel
Section of Nephrology, Department of Medicine.
Lloyd G
LG
Cantley
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015999:Multivariate Analysis; D010641:Phenotype; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D015854:Up-Regulation
D016178:Granulocyte-Macrophage Colony-Stimulating Factor
cell signaling; immunology; ischemia/reperfusion; ischemic renal failure; macrophages; renal proximal tubule cell