Reduced macrophage recruitment, proliferation, and activation in colony-stimulating factor-1-deficient mice results in decreased tubular apoptosis during renal inflammation

Kidney tubular epithelial cell (TEC) death may be dependent on the number and activation state of. macrophages (M(P) during inflammation. Our prior studies indicate that activated Mphi release soluble mediators that incite TEC death, and reducing intrarenal Mphi during kidney disease diminishes TEC apoptosis. CSF-1 is required for Mphi proliferation and survival. We hypothesized that in the absence of CSF-1, Mphi-mediated TEC apoptosis would be prevented during renal inflammation. To test this hypothesis, we evaluated renal inflammation during unilateral ureter obstruction in CSF-1-deficient (Csf1(op)/Csf1(op)) mice. We detected fewer Mphi and T cells and less apoptotic TEC in the obstructed kidneys of Csf1(op)/Csf1(op) mice compared with wild-type (WT) mice. The decrease in intrarenal Mphi resulted from diminished recruitment and proliferation, not enhanced apoptosis. CSF-1 enhanced Mphi activation. There were far fewer activated (CD69, CD23, Ia, surface expression) Mphi in obstructed CSF-1-deficient compared with WT obstructed kidneys. Similarly, bone marrow Mphi preincubated with anti-CSF-1. receptor Ab or anti-CSF-1 neutralizing Ab were resistant to LPS- and IFN-gamma-induced activation. We detected fewer apoptotic-inducing molecules (reactive oxygen species, TNF-alpha, inducible NO synthase) in 1) Mphi propagated from obstructed Csf1(op)/Csf1(op) compared with WT kidneys, and 2) WT bone marrow Mphi blocked with anti-CSF-1 receptor or anti-CSF-1 Ab compared with the isotype control. Furthermore, blocking CSF-1 or the CSF-1 receptor induced less TEC apoptosis than the isotype control. We suggest that during renal inflammation, CSF-1 mediates Mphi recruitment, proliferation, activation, and, in turn, TEC apoptosis.