Granulin exacerbates lupus nephritis via enhancing macrophage M2b polarization

PLoS One. 2013 Jun 5;8(6):e65542. doi: 10.1371/journal.pone.0065542. Print 2013.

Abstract

Background and aims: Lupus nephritis (LN), with considerable morbidity and mortality, is one of the most severe manifestations of systemic lupus erythematosus (SLE). Yet, the pathogenic mechanisms of LN have not been clearly elucidated, and efficient therapies are still in great need. Granulin (GRN), a multifunctional protein linked to inflammatory diseases, has recently been reported to correlate with the disease activity of autoimmune diseases. However, the role of GRN in the pathogenic process of LN still remains obscure. In this study, we explored its potential role and underlying mechanism in the pathogenesis of LN.

Methodology/principal findings: We found that serum GRN levels were significantly up-regulated and were positively correlated with the severity of LN. Overexpression of GRN in vivo by transgenic injection remarkably exacerbated LN, whereas down-regulation of GRN with shRNA ameliorated LN, firmly demonstrating the critical role of GRN in the pathogenesis of LN. Notably, macrophage phenotype analysis revealed that overexpression of GRN could enhance macrophage polarization to M2b, a key mediator of the initiation and progression of LN. On the contrary, down-regulation of GRN resulted in impaired M2b differentiation, thus ameliorating LN. Moreover, we found that MAPK signals were necessary for the effect of GRN on macrophage M2b polarization.

Conclusion/significance: We first demonstrated that GRN could aggravate lupus nephritis (LN) via promoting macrophage M2b polarization, which might provide insights into the pathogenesis of LN as well as potential therapeutic strategies against LN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Polarity
  • Cells, Cultured
  • Female
  • Intercellular Signaling Peptides and Proteins / blood*
  • Kidney / immunology
  • Kidney / physiopathology
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / pathology
  • Lupus Nephritis / blood
  • Lupus Nephritis / immunology
  • Lupus Nephritis / pathology
  • MAP Kinase Signaling System
  • Macrophages / immunology*
  • Macrophages / physiology
  • Mice
  • Mice, Inbred BALB C
  • Progranulins
  • Up-Regulation

Substances

  • Intercellular Signaling Peptides and Proteins
  • Progranulins

Grant support

This work was supported by grants from the National Natural Science Foundation of China (30890141, 81273300), Major State Basic Research Development Program of China (2013CB530501), Jiangsu Provincial Innovative Research Team, Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT-IRT1075), Jiangsu "333" project of cultivation of high-level talents, Qing Lan Project of the Jiangsu higher education institutions, Jiangsu "Pan-Deng" Project (BK2010004), Shanghai STC grant (10JC1401400). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.