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Enhanced response of macrophages to CSF-1 in autoimmune mice: a gene transfer strategy
1Immunogenetics and Transplantation, Renal Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Abstract:
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.
Insights
Mice with the MRL background show increased macrophage (M phi) response to CSF-1, leading to kidney injury. This heightened M phi proliferation in MRL strains contributes to autoimmune lupus nephritis development.
Area of Science:
- Immunology
- Nephrology
- Genetics
Background:
- Mice with the MRL background are genetically predisposed to autoimmune lupus nephritis.
- The lpr mutation exacerbates renal injury in MRL mice, with macrophages (M phi) being prominent.
- Colony-stimulating factor 1 (CSF-1) is associated with M phi accumulation and renal injury in MRL-lpr mice.
Purpose of the Study:
- To investigate the hypothesis that MRL macrophages respond more readily to CSF-1 than those from normal strains.
- To elucidate the role of CSF-1 in M phi accumulation and kidney injury in MRL mice.
Main Methods:
- Assessed proliferation of glomerular and bone marrow M phi (BMM phi) from MRL-lpr mice in response to CSF-1.
- Compared MRL BMM phi proliferation to normal strains (C3H, BALB/c) and C3H-lpr mice.
- Evaluated CSF-1 receptor expression modulation by CSF-1 in MRL and C3H BMM phi.
- Utilized a gene transfer strategy with CSF-1-producing tubular epithelial cells (CSF-1-TECs) and BMM phi to induce kidney lesions.
Main Results:
- MRL-lpr glomerular and bone marrow M phi proliferated similarly to CSF-1.
- MRL BMM phi exhibited more vigorous proliferation to CSF-1 compared to C3H, BALB/c, and C3H-lpr strains.
- CSF-1 receptor modulation by CSF-1 was more rapid in MRL than C3H BMM phi.
- Co-implantation of CSF-1-TECs and BMM phi led to greater M phi accumulation and lesion development in MRL +/+ mice than in C3H +/+ mice.
Conclusions:
- MRL macrophages demonstrate a heightened proliferative response to CSF-1 compared to other strains.
- This enhanced M phi response to CSF-1 in MRL mice is a key factor in the significant M phi accumulation observed in the MRL-lpr kidney.
- The findings suggest a critical role for CSF-1-driven M phi accumulation in the pathogenesis of lupus nephritis in MRL mice.