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 phi) during inflammation. Our prior studies indicate that activated M phi release soluble mediators that incite TEC death, and reducing intrarenal M phi during kidney disease diminishes TEC apoptosis. CSF-1 is required for M phi proliferation and survival. We hypothesized that in the absence of CSF-1, M phi-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 M phi 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 M phi resulted from diminished recruitment and proliferation, not enhanced apoptosis. CSF-1 enhanced M phi activation. There were far fewer activated (CD69, CD23, Ia, surface expression) M phi in obstructed CSF-1-deficient compared with WT obstructed kidneys. Similarly, bone marrow M phi 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) M phi propagated from obstructed Csf1(op)/Csf1(op) compared with WT kidneys, and 2) WT bone marrow M phi 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 M phi recruitment, proliferation, activation, and, in turn, TEC apoptosis.