Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation.

Ewelina Dobosz,Maciej Lech,Vivian Würf,Andrea Ribeiro,Christoph Schmaderer,Marta Wadowska,Jerzy Kotlinowski,Mingui Fu,Joanna Koziel,Georg Lorenz,Jan Potempa

doi:10.1242/dmm.047589

Abstract

ABSTRACTMyeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined.Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as Baff, Il5, Il9 and Cd40L, affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance.Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity.

Highlights

IntroductionMonocyte chemoattractant protein-1 induced protein-1 (MCPIP1)-deficient mice die prematurely and display signs of severe multiorgan inflammation (Liang et al, 2010; Matsushita et al, 2009; Miao et al, 2013)
As primary macrophage activation syndrome (MAS) is a severe complication of rheumatic disease in childhood, which is characterized by natural killer cell defects, uncontrolled activation of macrophages, high fever and a systemic cytokine storm, we investigated a cohort of 8-week-old Mcpip1fl/flLysMcre+ mice for signs of spontaneous autoinflammation
Monocyte chemoattractant protein-1 induced protein-1 (MCPIP1) is a member of a CCCH zinc-finger-containing protein family, and MCPIP1 was identified as an MCP-1-induced gene in human monocytes (Zhou et al, 2006)

Summary

Introduction

MCPIP1-deficient mice die prematurely and display signs of severe multiorgan inflammation (Liang et al, 2010; Matsushita et al, 2009; Miao et al, 2013). They develop hyper-responsiveness upon exposure to some pathogen-associated molecular patterns (Liang et al, 2010; Matsushita et al, 2009). Despite the general agreement that MCPIP1 is a powerful negative regulator of inflammation, its role in cell-specific responses and autoimmunity remains poorly understood

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