Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.
Fibrocytes are a distinct population of bloodborne cells that share markers of leukocytes as well as mesenchymal cells. We hypothesized that CCR7-positive fibrocytes migrate into the kidney in response to secondary lymphoid tissue chemokine (SLC/CCL21) and contribute to renal fibrosis. To investigate this hypothesis, renal fibrosis was induced by unilateral ureteral obstruction in mice. A considerable number of fibrocytes dual-positive for CD45 and type I collagen (ColI) or CD34 and ColI infiltrated the interstitium, reaching a peak on day 7. Most fibrocytes were positive for CCR7, and CCL21/CCR7 blockade reduced the number of infiltrating fibrocytes. CCL21 and MECA79 dual-positive vessels were also detected in the interstitium. The blockade of CCL21/CCR7 signaling by anti-CCL21 antibodies reduced renal fibrosis, which was confirmed by a decrease in fibrosis in CCR7-null mice with concomitant reduction in renal transcripts of pro alpha1 chain of ColI and TGF-beta1. The number of F4/80-positive macrophages decreased along with renal transcripts of monocyte chemoattractant protein 1 (MCP-1/CCL2) after the blockade of CCL21/CCR7 signaling. These findings suggest that CCR7-positive fibrocytes infiltrate the kidney via CCL21-positive vessels, thereby contributing to the pathogenesis of renal fibrosis. Thus, the CCL21/CCR7 signaling of fibrocytes may provide therapeutic targets for combating renal fibrosis.
Sakai
Norihiko
N
Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, and Division of Blood Purification, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Wada
Takashi
T
Yokoyama
Hitoshi
H
Lipp
Martin
M
Ueha
Satoshi
S
Matsushima
Kouji
K
Kaneko
Shuichi
S
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014513:Ureter / Q000601:surgery
D000906:Antibodies; C515478:CCL21 protein, human; C515370:CCR7 protein, human; C491768:Ccl2 protein, mouse; C515479:Ccl21c protein, mouse; C515371:Ccr7 protein, mouse; D018932:Chemokine CCL2; D054421:Chemokine CCL21; D019742:Chemokines, CC; D054400:Receptors, CCR7; D019707:Receptors, Chemokine