C1q-mediated repression of human monocytes is regulated by leukocyte-associated Ig-like receptor 1 (LAIR-1).

Myoungsun Son,Betty Diamond

doi:10.2119/molmed.2014.00185

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by abnormal function of both the innate and the adaptive immune system, leading to a loss of tolerance to self-antigens. Monocytes are a key component of the innate immune system and are efficient producers of multiple cytokines. In SLE, inappropriate activation of monocytes is thought to contribute to the loss of self-tolerance. In this study, we demonstrate that type 1 interferon (IFN) production by CpG-challenged monocytes can be suppressed by C1q through activating leukocyte-associated Ig-like receptor-1 (LAIR-1), which contains immunoreceptor tyrosine-based inhibition motifs (ITIMs). The phosphorylation of LAIR-1 and the interaction of LAIR-1 with SH2 domain-containing protein tyrosine phosphatase-1 (SHP-1) were enhanced after LAIR-1 engagement by C1q. Moreover, engagement of LAIR-1 by C1q inhibited nuclear translocation of interferon regulatory factor (IRF)-3 and IRF5 in CpG-stimulated monocytes. These data suggest a model in which LAIR-1 engagement by C1q helps maintain monocyte tolerance, specifically with respect to Toll-like receptor-9-mediated monocyte activation.

Highlights

Studies on the pathogenesis of systemic lupus erythematosus (SLE) focused on the adaptive immune system, since B and T lymphocyte abnormalities were thought to be the primary cause of autoimmunity
We have previously shown that the addition of C1q to human plasmacytoid DCs (pDCs) inhibited IFNα production after CpG stimulation in a dose-dependent fashion
This inhibition was reversed by soluble LAIR-2 [34], suggesting that the inhibitory effects of C1q required that C1q bind to LAIR-1

Summary

Introduction

Studies on the pathogenesis of systemic lupus erythematosus (SLE) focused on the adaptive immune system, since B and T lymphocyte abnormalities were thought to be the primary cause of autoimmunity. It is increasingly recognized that components of the innate immune system play an essential role in SLE [1,2,3,4,5]. Monocytes are myeloid cells that play a key role in innate immunity and are efficient producers of proinflammatory cytokines and type 1 interferons (IFNs), IFNα and IFNβ, when stimulated by pathogen-associated molecular patterns (PAMPs) such as unmethylated bacterial DNA or damage-associated molecular patterns (DAMPs) such as apoptotic debris [2,5,6]. Increased levels of type 1 IFN are seen in virtually all pediatric patients and a substantial percentage of adult patients. High IFN levels are a feature of some unaffected first-degree relatives as well [7,8]

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Discussion

Conclusion