Inhibition of CCL1-CCR8 Interaction Prevents Aggregation of Macrophages and Development of Peritoneal Adhesions

Abstract

Peritoneal adhesions are a significant complication of surgery and visceral inflammation; however, the mechanism has not been fully elucidated. The aim of this study was to clarify the mechanism of peritoneal adhesions by focusing on the cell trafficking and immune system in the peritoneal cavity. We investigated the specific recruitment of peritoneal macrophages (PMφ) and their expression of chemokine receptors in murine models of postoperative and postinflammatory peritoneal adhesions. PMφ aggregated at the site of injured peritoneum in these murine models of peritoneal adhesions. The chemokine receptor CCR8 was up-regulated in the aggregating PMφ when compared with naive PMφ. The up-regulation of CCR8 was also observed in PMφ, but not in bone marrow-derived Mφ, treated with inflammatory stimulants including bacterial components and cytokines. Importantly, CCL1, the ligand for CCR8, a product of both PMφ and peritoneal mesothelial cells (PMCs) following inflammatory stimulation, was a potent enhancer of CCR8 expression. Cell aggregation involving PMφ and PMCs was induced in vitro in the presence of CCL1. CCL1 also up-regulated mRNA levels of plasminogen activator inhibitor-1 in both PMφ and PMCs. CCR8 gene-deficient mice or mice treated with anti-CCL1-neutralizing Ab exhibited significantly reduced postoperational peritoneal adhesion. Our study now establishes a unique autocrine activation system in PMφ and the mechanism for recruitment of PMφ together with PMCs via CCL1/CCR8, as immune responses of peritoneal cavity, which triggers peritoneal adhesions.

CCR8 Signaling Influences Toll-Like Receptor 4 Responses in Human Macrophages in Inflammatory Diseases

“…Statistical power is described as follows: NS, P Ͼ 0.05; *, P Յ 0.05 to P Ն 0.01; **, P Յ 0.01 to P Ն 0.001; and ***, P Ͻ 0.001. is in alignment with observations on multiple sclerosis (MS) lesions from patients who previously has been demonstrated to express CCR8 and correlated with demyelization activity in the brain and in foam cells in arthrosclerosis plaque (16,34). In preclinical models of peritoneal adhesion, macrophages were described to produce CCL1 and respond in an autocrine fashion through CCR8 (17). These cells regulate expression of several adhesion molecules in the integrin family, allowing formation of aggregates of cells that over time result in fibrous tissue (17).…”

“…In preclinical models of peritoneal adhesion, macrophages were described to produce CCL1 and respond in an autocrine fashion through CCR8 (17). These cells regulate expression of several adhesion molecules in the integrin family, allowing formation of aggregates of cells that over time result in fibrous tissue (17). In context of this observation, it is interesting that adhesion molecule expression on in vitro-generated human M2 macrophages (M-CSF derived) is more sensitive to CCL1 than that on M1 macrophages (GM-CSF derived).…”

Blockade of CCL1 Inhibits T Regulatory Cell Suppressive Function Enhancing Tumor Immunity without Affecting T Effector Responses

“…This raises the question whether newly converted Tregs secreting CCL1 play a role in Treg homing and accumulation in the tumor. Paracrine signaling is probable because other immune cells also express CCR8 and migrate to CCL1, cutaneous memory subsets of CD4 + and CD8 + cells (39), NK cells (40,41), Langerhanstype DCs (42), peritoneal macrophages (43), and Th2 cells (44). This evidence of the role of ITGaE and CCL1 in Treg biology led us to investigate these targets further.…”

Deficiency of Chemokine Receptor CCR1 Causes Osteopenia Due to Impaired Functions of Osteoclasts and Osteoblasts

“…The real-time quantitative PCR analyses were performed using the ABI 7700 sequence detector system with SYBR Green (Applied Biosystems, Foster City, CA). The sequences were amplified for 40 cycles under the following conditions: denaturation at 95°C for 15 s, annealing at 60°C for 30 s, and extension at 72°C for 45 s with primers for the chemokine receptors as previously reported (17). Gene expression levels were compared with Gapdh gene expression by the 2 Ϫ⌬(Ct) method.…”