Role of CC Chemokine Receptor 2 in Bone Marrow Cells in the Recruitment of Macrophages into Obese Adipose Tissue

Ayaka Ito,Takayoshi Suganami,Akira Yamauchi,Mikako Degawa-Yamauchi,Miyako Tanaka,Ryuji Kouyama,Yuko Kobayashi,Nao Nitta,Kazuki Yasuda,Yukio Hirata,William A Kuziel,Motohiro Takeya,Shiro Kanegasaki,Yasutomi Kamei,Yoshihiro Ogawa

doi:10.1074/jbc.m804220200

Abstract

The MCP-1 (monocyte chemoattractant protein-1)/CCR2 (CC motif chemokine receptor-2) pathway may play a role in macrophage infiltration into obese adipose tissue. Here we investigated the role of CCR2 in the recruitment of bone marrow-derived macrophages into obese adipose tissue in vitro and in vivo. Using the TAXIScan device, which can measure quantitatively the directionality and velocity of cell migration at time lapse intervals in vitro, we demonstrated that bone marrow cells (BMCs) from wild type mice migrate directly toward MCP-1 or culture medium conditioned by adipose tissue explants of genetically obese ob/ob mice, which are efficiently suppressed by pharmacological blockade of CCR2 signaling. The number of F4/80-positive macrophages was reduced in the adipose tissue from high fat diet-fed obese KKAy or ob/ob mice treated with a CCR2 antagonist propagermanium relative to vehicle-treated groups. We also found that the number of macrophages is reduced in the adipose tissue from ob/ob mice reconstituted with CCR2(-/-) BMCs (ob/ob + CCR2(-/-) BMCs) relative to those with CCR2+/+ BMCs (ob/ob + CCR2+/+ BMCs). Expression of mRNAs for CD11c and TLR4 (Toll-like receptor 4) markers of proinflammatory M1 macrophages was also decreased in the adipose tissue from ob/ob + CCR2(-/-) BMCs relative to ob/ob + CCR2+/+ BMCs, whereas mannose receptor and CD163, markers of anti-inflammatory M2 macrophages, were unchanged. This study provides in vivo and in vitro evidence that CCR2 in bone marrow cells plays an important role in the recruitment of macrophages into obese adipose tissue.

Highlights

The MCP-1/CCR2 (CC motif chemokine receptor-2) pathway may play a role in macrophage infiltration into obese adipose tissue
Using the TAXIScan device, which can measure quantitatively the directionality and velocity of cell migration at time lapse intervals in vitro, we demonstrated that bone marrow cells (BMCs) from wild type mice migrate directly toward MCP-1 or culture medium conditioned by adipose tissue explants of genetically obese ob/ob mice, which are efficiently suppressed by pharmacological blockade of CCR2 signaling
Using an in vitro co-culture system composed of adipocytes and macrophages, we have demonstrated that a paracrine loop involving saturated fatty acids and tumor necrosis factor-␣ derived from adipocytes and macrophages, respectively, establishes a vicious cycle that augments the inflammatory changes (i.e. marked up-regulation of proinflammatory adipocytokines, such as MCP-1 and tumor necrosis factor-␣, and down-regulation of adiponectin) [4, 5]

Summary

Introduction

The MCP-1 (monocyte chemoattractant protein-1)/CCR2 (CC motif chemokine receptor-2) pathway may play a role in macrophage infiltration into obese adipose tissue. We investigated the role of CCR2 in the recruitment of bone marrow-derived macrophages into obese adipose tissue in vitro and in vivo.

Results

Conclusion