title: Dual effect of chemokine CCL7/MCP-3 in the development of renal tubulointerstitial fibrosis.
abstract: Most end-stage renal disease kidneys display accumulation of extracellular matrix (ECM) in the renal tubular compartment (tubular interstitial fibrosis - TIF) which is strongly correlated with the future loss of renal function. Although inflammation is a key event in the development of TIF, it can also have a beneficial anti-fibrotic role depending in particular on the stage of the pathology. Chemokines play an important role in monocyte extravasation in the inflammatory process. CCL2 has already been shown to be involved in the development of TIF but CCL7, a close relative of CCL2 and able to bind to similar receptors, has not been studied in renal disease. We therefore studied chemokine CCL7 in a model of unilateral ureteral obstruction (UUO)-induced TIF. We observed that the role of CCL7 differs depending on the stage of the pathology. In early stages (0-8 days), CCL7 deficient (CCL7-KO) mice displayed attenuated TIF potentially involving two mechanisms: an early (0-3 days) decrease of inflammatory cell infiltration followed (3-8 days) by a decrease in tubular ECM production independent of inflammation. In contrast, during later stages of obstruction (10-14 days), CCL7-KO mice displayed increased TIF which was again associated with reduced inflammation. Interestingly, the switch between this anti- to profibrotic effect was accompanied by an increased influx of immunosuppressive regulatory T cells. In conclusion, these results highlight for the first time a dual role for CCL7 in the development of renal TIF, deleterious in early stages but beneficial during later stages.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France. julien.gonzalez@inserm.fr
authors.forename: Julien
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Sofia
authors.initials: S
authors.lastname: Mouttalib
authors.forename: Christine
authors.initials: C
authors.lastname: Delage
authors.forename: Denis
authors.initials: D
authors.lastname: Calise
authors.forename: Jean-José
authors.initials: JJ
authors.lastname: Maoret
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pradère
authors.forename: Julie
authors.initials: J
authors.lastname: Klein
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Buffin-Meyer
authors.forename: Betty
authors.initials: B
authors.lastname: Van der Veen
authors.forename: Israel F
authors.initials: IF
authors.lastname: Charo
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
authors.forename: Johan
authors.initials: J
authors.lastname: Duchene
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Bascands
authors.forename: Joost-Peter
authors.initials: JP
authors.lastname: Schanstra
mesh_terms: D000818:Animals; D002460:Cell Line; D054410:Chemokine CCL7 / Q000235:genetics / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D013997:Time Factors
chemical_list: C515450:CCL7 protein, human; C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D003094:Collagen
keywords: Fibrosis; Inflammation; Kidney