Reduced Macrophage Recruitment, Proliferation, and Activation in Colony-Stimulating Factor-1-Deficient Mice Results in Decreased Tubular Apoptosis During Renal Inflammation

Abstract

Kidney tubular epithelial cell (TEC) death may be dependent on the number and activation state of macrophages (Mφ) during inflammation. Our prior studies indicate that activated Mφ release soluble mediators that incite TEC death, and reducing intrarenal Mφ during kidney disease diminishes TEC apoptosis. CSF-1 is required for Mφ proliferation and survival. We hypothesized that in the absence of CSF-1, Mφ-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 (Csf1op/Csf1op) mice. We detected fewer Mφ and T cells and less apoptotic TEC in the obstructed kidneys of Csf1op/Csf1op mice compared with wild-type (WT) mice. The decrease in intrarenal Mφ resulted from diminished recruitment and proliferation, not enhanced apoptosis. CSF-1 enhanced Mφ activation. There were far fewer activated (CD69, CD23, Ia, surface expression) Mφ in obstructed CSF-1-deficient compared with WT obstructed kidneys. Similarly, bone marrow Mφ preincubated with anti-CSF-1 receptor Ab or anti-CSF-1 neutralizing Ab were resistant to LPS- and IFN-γ-induced activation. We detected fewer apoptotic-inducing molecules (reactive oxygen species, TNF-α, inducible NO synthase) in 1) Mφ propagated from obstructed Csf1op/Csf1op compared with WT kidneys, and 2) WT bone marrow Mφ 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 Mφ recruitment, proliferation, activation, and, in turn, TEC apoptosis.

C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist

“…Furthermore, we found that apoptosis is strongly correlated with renal disease severity in MRL/lpr mice, supporting the relevance of apoptosis to lupus nephritis. The striking correlation with monocyte/macrophage numbers (r=0.951) is particularly interesting, and is in keeping with the observations of Lenda et al [51,52], in which macrophage-directed apoptosis appears to be relevant in models of progressive tubulointerstitial damage, such as obstructive nephropathy, and in these same MRL/lpr mice.…”

Distinct In Vivo Roles of Colony-Stimulating Factor-1 Isoforms in Renal Inflammation

“…To answer this question, we analyzed the accumulation and activation of M, as well as M-mediated TEC apoptosis during renal inflammation induced by UUO. We compared TgC/ϩ and WT kidneys 3 days after UUO, since at this time intrarenal M accumulation is florid and hydronephrosis is less severe as compared with later time points (12). Consistent with previous findings, we detected twice the numbers of M accumulated in WT-obstructed kidneys (interstitium, glomeruli) as compared with Csf1 op /Csf1 op -obstructed kidneys (Fig.…”

“…Furthermore, CSF-1-deficient MRL-Fas lpr mice are protected from nephritis and the systemic illness characteristic of the MRLFas lpr wild-type (WT) strain (8). Similarly, in unilateral ureteral obstruction (UUO) in which blocking the flow of urine results in a florid M infiltration into the renal interstitium that leads to tubular damage and interstitial fibrosis (9 -11), we determined that renal injury is dependent on CSF-1 (12). In the CSF-1 null mice, fewer M accumulate within the kidney, and moreover, they do not proliferate and fewer are activated than in WT mice.…”

Circulating CSF-1 Promotes Monocyte and Macrophage Phenotypes that Enhance Lupus Nephritis

“…42 We collected 0.5 ϫ 10 6 to 1.0 ϫ 10 6 total kidney cells and 0.5 ϫ 10 5 to 1.0 ϫ 10 5 blood leukocytes/BM Mo using a FACSCalibur (Becton Dickinson, San Jose, CA) and analyzed the data using Flowjo software (Tree Star, Palo Alto, CA). The BM Mo and circulating Mo were characterized by gating on the SSC low CD11b high population.…”

“…9,10 Moreover, CSF-1-deficient mice (Csf1 op/op ;MRL-Fas lpr ) are protected from kidney disease and systemic illness. 11,12 However, the Csf1 op/op ;MRLFas lpr mice are frail and have skeletal abnormalities and numerous other defects. [13][14][15][16] Thus, it is possible that the effect of deleting CSF-1 on lupus in MRL-Fas lpr mice is, at least in part, not directly related to the reduction of Mø.…”