Late Onset of Treatment with a Chemokine Receptor CCR1 Antagonist Prevents Progression of Lupus Nephritis in MRL-Fas(lpr) Mice

Abstract

Abstract. Slowly progressive renal injury is the major cause for ESRD. The model of progressive immune complex glomerulonephritis in autoimmune MRL lpr/lpr mice was used to evaluate whether chemokine receptor CCR1 blockade late in the disease course can affect progression to renal failure. Mice were treated with subcutaneous injections of either vehicle or BX471, a nonpeptide CCR1 antagonist, three times a week from week 20 to 24 of age. BX471 improved blood urea nitrogen levels (BX471, 35.1 Ϯ 5.3; vehicle, 73.1 Ϯ 39.6 mg/dl; P Ͻ 0.05) and reduced the amount of ERHR-3 macrophages, CD3 lymphocytes, Ki-67 positive proliferating cells, and ssDNA positive apoptotic cells in the interstitium but not in glomeruli. Cell transfer studies with fluorescence-labeled T cells that were pretreated with either vehicle or BX471 showed that BX471 blocks macrophage and T cell recruitment to the renal interstitium of MRL lpr/lpr mice. This was associated with reduced renal expression of CC chemokines CCL2, CCL3, CCL4, and CCL5 and the chemokine receptors CCR1, CCR2, and CCR5. Furthermore, BX471 reduced the extent of interstitial fibrosis as evaluated by interstitial smooth muscle actin expression and collagen I deposits, as well as mRNA expression for collagen I and TGF-␤. BX471 did not affect serum DNA autoantibodies, proteinuria, or markers of glomerular injury in MRL lpr/lpr mice. This is the first evidence that, in advanced chronic renal injury, blockade of CCR1 can halt disease progression and improve renal function by selective inhibition of interstitial leukocyte recruitment and fibrosis.

Activated Renal Macrophages Are Markers of Disease Onset and Disease Remission in Lupus Nephritis

“…Interestingly, CCR1, a receptor that can interact with both CCL3 and CCL9, was up-regulated only in established disease. This is consistent with studies showing that CCR1 is involved mainly in interstitial infiltration that occurs in the later stages of disease (29).…”

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

“…For example, treatment with oral fingolimod (FTY720) and with the targeted murine C3 complement inhibitor CR2-Crry was found to be more effective in ameliorating glomerular injury than in controlling interstitial infiltrates and lesions (37,38). Otherwise, blockade of CCR1 could selectively halt interstitial leukocyte recruitment and fibrosis but not glomerular injury in MRL/lpr mice (39). Some published studies demonstrated that CD4ϩ T cells were major infiltrating cells in glomeruli, whereas F4/80ϩ macrophages were predominant in the interstitium of both MRL/lpr mice and lupus-prone NZM2328 mice (40,41).…”

The Pathogenesis of Lupus Nephritis

“…63 For example, the chemokine CCL2 recruits CCR2 + proinflammatory macrophages and T cells into the glomerulus and the tubulointerstitium, 64,65 whereas CCR1 + cells only recruit to the interstitial compartment and not to the glomerulus in LN. 66 Other leukocyte subsets involve other chemokines and chemokine receptors for their recruitment into the kidney. 63,67 Leukocyte recruitment is tightly regulated.…”