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Limits Macrophage Expansion in MRL-Faslpr Autoimmune Interstitial Nephritis: A Negative Regulatory Pathway1
Laboratory of Autoimmune Disease, Renal Division, Brigham and Women’s Hospital, Boston, MA 02115
IFN-
is capable of enhancing and limiting inflammation.
Therefore, an increase in IFN- in autoimmune
MRL-Faslpr mice could exacerbate or thwart
renal injury. We have established a retroviral gene transfer approach
to incite interstitial nephritis in MRL-Faslpr
mice that is rapid, enduring, and circumscribed. Renal tubular
epithelial cells (TEC) were genetically modified to secrete macrophage
(M
) growth factors (CSF-1-TEC, GM-CSF-1-TEC) and infused under the
renal capsule. To determine the impact of IFN- in M growth
factor-incited renal injury, we constructed a
MRL-Faslpr IFN--receptor
(IFN-R)-deficient strain. Gene transfer of CSF-1 or GM-CSF incited
more severe interstitial nephritis in IFN-R-deficient than in
IFN-R-intact MRL-Faslpr mice, consisting of
an increase of M. To determine the mechanism responsible for the
increase in M in IFN-R-deficient
MRL-Faslpr mice, we evaluated M
proliferation, apoptosis, and recruitment. Proliferation of bone marrow
M from IFN-R-intact MRL-Faslpr
costimulated with CSF-1 or GM-CSF and IFN- was reduced twofold,
while the IFN-R-deficient MRL-Faslpr bone
marrow M remained stable. Furthermore, we detected more
proliferating and fewer apoptotic M within the interstitium in
IFN-R-deficient MRL-Faslpr mice. Using
unilateral ureteral ligation we established that IFN-R signaling
does not alter M recruitment into the kidney. Thus, the increase in
M elicited by M growth factors in IFN-R-deficient
MRL-Faslpr mice is a result of enhanced
proliferation and decreased apoptosis, and is independent of
recruitment. Taken together, we suggest that IFN- provides a
negative regulatory pathway capable of limiting M-mediated renal
inflammation.
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