CCR2 contributes to the recruitment of monocytes and leads to kidney inflammation and fibrosis development.
Chemokines are a large family of proteins that, once associated to its receptor on leukocytes, stimulate their movement and migration from blood to tissues. Once in the tissue, immune cells trigger inflammation that, when uncontrolled, leads to fibrosis development. Among the immune cells, macrophages take a special role in fibrosis formation, since macrophage depletion reflects less collagen deposition. The majority of tissue macrophages is derived from monocytes, especially monocytes expressing the chemokine receptor CCR2. Here, we investigated the role of infiltrating CCR2+cells in the development of fibrosis, and specifically, the dynamic of infiltration of these cells into kidneys under chronic obstructive lesion. Using liposome-encapsulated clodronate, we observed that macrophage depletion culminated in less collagen deposition and reduced chemokines milieu that were released in the damaged kidney after obstructive nephropathy. We also obstructed the kidneys of CCL3-/-, CCR2-/-, CCR4-/-, CCR5-/-, and C57BL/6 mice and we found that among all animals, CCR2-/-mice demonstrated the more robust protection, reflected by less inflammatory and Th17-related cytokines and less collagen formation. Next we evaluated the dynamic of CCR2+/rfpcell infiltration and we observed that they adhere onto the vessels at early stages of disease, culminating in increased recruitment of CCR2+/rfpcells at later stages. On the other hand, CCR2rfp/rfpanimals exhibited less fibrosis formation and reduced numbers of recruited cells at later stages. We have experimentally demonstrated that inflammatory CCR2+cells that reach the injured kidney at initial stages after tissue damage are responsible for the fibrotic pattern observed at later time points in the context of UUO.
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil. tarcio.tb@gmail.com.
Tarcio Teodoro
TT
Braga
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
Matheus
M
Correa-Costa
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
Reinaldo Correia
RC
Silva
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
Mario Costa
MC
Cruz
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
Meire Ioshie
MI
Hiyane
Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, 14049-900, Brazil.
Joao Santana
JS
da Silva
Department of Biochemistry, Institute of Chemistry University of São Paulo (USP), São Paulo, Brazil.
Katia Regina
KR
Perez
Department of Biochemistry, Institute of Chemistry University of São Paulo (USP), São Paulo, Brazil.
Iolanda Midea
IM
Cuccovia
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.|Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.|Renal Pathophysiology Laboratory (LIM16), Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
Niels Olsen Saraiva
NOS
Camara
D000818:Animals; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D054390:Receptors, CCR2 / Q000378:metabolism*
C515335:Ccr2 protein, mouse; D016207:Cytokines; D054390:Receptors, CCR2; D003094:Collagen
CCR2+ monocytes; Fibrosis; UUO