Enhanced response of macrophages to CSF-1 in autoimmune mice: a gene transfer strategy.
Mice with the MRL background have a genetic propensity for autoimmune lupus nephritis. The lpr mutation on the MRL, but not the C3H background, induces rapid and fatal renal injury in which macrophages (M phi) are prominent. We previously established that CSF-1 accompanies M phi accumulation in the kidney of MRL-lpr mice. Furthermore, CSF-1 introduced into the kidney incites renal injury in mice with the lpr mutation, but not congenic strains. Notably, CSF-1 induces more severe tissue injury in MRL-lpr than in C3H-lpr mice. We hypothesized that M phi from the MRL background respond more readily to CSF-1 than normal strains. We establish herein the following: 1) glomerular M phi and bone marrow M phi (BMM phi) from MRL-lpr mice proliferate similarly to CSF-1; 2) MRL BMM phi proliferate more vigorously to CSF-1 than normal strains (C3H, BALB/c) or another strain with lpr (C3H-lpr); and 3) modulation of CSF-1 receptor expression by CSF-1 is more rapid in MRL than C3H BMM phi. We used a gene transfer strategy to deliver CSF-1 into the kidney to evaluate M phi response to CSF-1. We genetically modified tubular epithelial cells to produce CSF-1 (CSF-1-TECs) and placed these cells with BMM phi under the renal capsule. CSF-1-TEC + BMM phi caused a greater accumulation of M phi in the implant site and interstitium of MRL +/+ than C3H +/+ mice. Furthermore, CSF-1-TEC + BMM phi caused a lesion consisting of M phi in MRL +/+ mice, extending from the implant into the adjacent cortex. We suggest that the response of MRL M phi to CSF-1 is responsible for the notable accumulation of M phi in the MRL-lpr kidney.
Moore
K J
KJ
Immunogenetics and Transplantation, Renal Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Naito
T
T
Martin
C
C
Kelley
V R
VR
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D004848:Epithelium / Q000637:transplantation; D005260:Female; D018014:Gene Transfer Techniques; D007678:Kidney Glomerulus / Q000473:pathology; D007684:Kidney Tubules / Q000637:transplantation; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology* / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains
D016173:Macrophage Colony-Stimulating Factor