Biliverdin Reductase A (BVRA) Mediates Macrophage Expression of Interleukin-10 in Injured Kidney.

Yujiao Guo,Wenhui Liao,Gang Xu,Rui Zeng,Meng Wang,Zhizhi Hu,Pengge Wang,Fengmin Zhu,Juan Yang,Guangchang Pei,Ying Yao

doi:10.3390/ijms160922621

Abstract

Biliverdin reductase A is an enzyme, with serine/threonine/tyrosine kinase activation, converting biliverdin (BV) to bilirubin (BR) in heme degradation pathway. It has been reported to have anti-inflammatory and antioxidant effect in monocytes and human glioblastoma. However, the function of BVRA in polarized macrophage was unknown. This study aimed to investigate the effect of BVRA on macrophage activation and polarization in injured renal microenvironment. Classically activated macrophages (M1macrophages) and alternative activation of macrophages (M2 macrophages) polarization of murine bone marrow derived macrophage was induced by GM-CSF and M-CSF. M1 polarization was associated with a significant down-regulation of BVRA and Interleukin-10 (IL-10), and increased secretion of TNF-α. We also found IL-10 expression was increased in BVRA over-expressed macrophages, while it decreased in BVRA knockdown macrophages. In contrast, BVRA over-expressed or knockdown macrophages had no effect on TNF-α expression level, indicating BVRA mediated IL-10 expression in macrophages. Furthermore, we observed in macrophages infected with recombinant adenoviruses BVRA gene, which BVRA over-expressed enhanced both INOS and ARG-1 mRNA expression, resulting in a specific macrophage phenotype. Through in vivo study, we found BVRA positive macrophages largely existed in mice renal ischemia perfusion injury. With the treatment of the regular cytokines GM-CSF, M-CSF or LPS, excreted in the injured renal microenvironment, IL-10 secretion was significantly increased in BVRA over-expressed macrophages. In conclusion, the BVRA positive macrophage is a source of anti-inflammatory cytokine IL-10 in injured kidney, which may provide a potential target for treatment of kidney disease.

Highlights

Macrophages belong to the mononuclear phagocytic system and its phenotype controls the homeostasis, immune responses and renal outcomes in normal and injured kidneys [1,2]
The untreated macrophages (M0) exhibited a mixture of round and spindle shaped cells; macrophages treated with GM-CSF (M1) showed a predominantly spindle-like shaped; macrophages treated with M-CSF (M2) changed their morphology into a predominantly circular shape (Figure 1A)
GM-CSF treated macrophages were associated with a significant down-regulation of anti-inflammatory cytokine IL-10, and increased secretion of pro-inflammatory cytokine TNF-α (Figure 1D,E)

Summary

Introduction

Macrophages belong to the mononuclear phagocytic system and its phenotype controls the homeostasis, immune responses and renal outcomes in normal and injured kidneys [1,2]. Plasticity and functional polarization are features of the mononuclear phagocyte system [3]. M1 macrophages represent the capacities to initiate inflammatory response, carry out anti-microbial function; M2 macrophages promote wound healing, antagonize destructive inflammation, and suppress adaptive immunity [5,6]. M1 phenotype macrophages induce type I helper T cell (Th1) response, typically activated by bacterial moieties (LPS) and Th1 cytokine interferon-gamma (IFN-γ), TNF-α or GM-CSF [7,8,9]. M2 phenotype macrophages are involved in type II helper cell (Th2)

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