CCR2 contributes to the recruitment of monocytes and leads to kidney inflammation and fibrosis development

Author(s)

Braga, Tarcio Teodoro ^[1] ; Correa-Costa, Matheus ^[1] ; Silva, Reinaldo Correia ^[1] ; Cruz, Mario Costa ^[1] ; Hiyane, Meire Ioshie ^[1] ; da Silva, Joao Santana ^[2] ; Perez, Katia Regina ^[3] ; Cuccovia, Iolanda Midea ^[3] ; Saraiva Camara, Niels Olsen ^{[1, 4, 5]}

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci 4, Dept Immunol, Lab Transplantat Immunobiol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Dept Biochem, Inst Chem, Sao Paulo - Brazil

^[4] Fed Univ Sao Paulo UNIFESP, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Renal Pathophysiol Lab LIM16, Fac Med, Sao Paulo - Brazil

• Document type: Journal article
• Source: INFLAMMOPHARMACOLOGY; v. 26, n. 2, p. 403-411, APR 2018.
• Web of Science Citations: 6

Abstract

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(+/rfp) cell infiltration and we observed that they adhere onto the vessels at early stages of disease, culminating in increased recruitment of CCR2(+/rfp) cells at later stages. On the other hand, CCR2(rfp/rfp) animals 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. (AU)

• FAPESP's process: 14/06992-8 - Cellular, molecular and immunological mechanisms generated through NLRP activation
• Grantee: Tárcio Teodoro Braga
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 12/02270-2 - New cellular, molecular and immunological mechanisms involved in acute and chronic renal injury: the search for new therapeutical approaches
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants