MCP-1/CCR2-dependent loop for fibrogenesis in human peripheral CD14-positive monocytes

Abstract

Monocyte/macrophage (Momicron) migration to sites of inflammation is a prerequisite cause of organ fibrosis. The recruitment and activation of Mo are regulated by C-C chemokines, especially monocyte chemoattractant protein-1 [(MCP-1)/CC chemokine ligand 2], which interacts with CC chemokine receptor 2 (CCR2). However, the mechanisms leading to fibrosis via MCP-1/CCR2 signaling in Mo remain to be investigated. The effect of MCP-1 on the expression of MCP-1, CCR2, transforming growth factor-beta1 (TGF-beta1), and type I collagen in circulating human CD14-positive Mo was investigated. In addition, the impact of MCP-1-specific or TGF-beta1-specific antisense (AS) phosphorothioate oligodeoxynucleotides (ODN) was examined to explore the involvement of autocrine/paracrine production of MCP-1 and TGF-beta1 by human CD14-positive Mo. Furthermore, specific CCR2 inhibitors were applied to examine the involvement of CCR2 signaling for the promotion of a fibrogenic response. The stimulation of Mo with MCP-1 increased mRNA levels of TGF-beta1 and a pro-alpha1 chain of type I collagen (COL1A1) as well as protein synthesis. Similarly, the expression of MCP-1 and CCR2 was enhanced by the stimulation with MCP-1 in dose- and time-dependent manners. This positive loop via MCP-1 was reduced by pretreatment with MCP-1-specific AS-ODN. It was also noted that pretreatment with TGF-beta1-specific AS-ODN partially reduced COL1A1 mRNA levels. Finally, transcripts of these molecules were suppressed by pretreatment with specific CCR2 inhibitors. The present study demonstrated that human peripheral CD14-positive Mo contribute directly to fibrogenesis by a MCP-1/CCR2-dependent amplification loop. These data suggest that fibrogenic processes in Mo regulated by MCP-1/CCR2 may be novel, therapeutic targets for combating organ fibrosis.

Evolution of the urinary proteome during human renal development and maturation: variations with gestational and postnatal age

“…CD14 is expressed on many cells and has been found to be elevated in the blood of patients with chronic renal disease, possibly as a marker for increased risk of death in patients on dialysis (21). Of note, CD14 and MCP-1 may interact to create fibrosis (22). In a study focusing on keloid formation, enhanced MCP-1 release by CD14+ cells augmented fibroblast proliferation (23).…”

Biomarkers for Lupus Nephritis

“…MCP-1 can also mediate a fibrogenic response (21)(22)(23), and increased uMCP-1 has been associated with histologic findings of scarring in kidney biopsies (16,24). Therefore, to use uMCP-1 as a biomarker for lupus nephritis, it will be important to be able to distinguish between uMCP-1 as representative of active renal inflammation or chronic fibrosis.…”

Dual Role of CCR2 in the Constitution and the Resolution of Liver Fibrosis in Mice

“…On the other hand, no significant up-regulation of CCR5 (another chemokine receptor commonly expressed in response to liver injury) 12,13 or its ligand CCL5 was found either in wild-type mice or in CCR2 Ϫ/Ϫ mutant mice, suggesting that the couple CCR5/ CCL5 does not mediate the response to the acute injury after CCl 4 injection. Finally, transforming growth factor-␤, a crucial factor for hepatic stellate cell activation 1 that has been shown to be up-regulated by MCP-1 via the CCR2 receptor, 14 is increased earlier in wild-type mice than in CCR2 Ϫ/Ϫ animals. Serum transaminases (alanine aminotransferases) were measured 12, 18, 24, and 48 hours after CCl 4 acute challenge and were found to be significantly lower in CCR2 Ϫ/Ϫ mutant mice than in wild-type littermates until 24 hours after injection ( Figure 1B).…”