DNA-Mediated Interferon Signature Induction by SLE Serum Occurs in Monocytes Through Two Pathways: A Mechanism to Inhibit Both Pathways.

Amit Porat,Eicke Latz,Czeslawa Kowal,Mingzhu He,Betty Diamond,Eitan Giat,Ilan Ben-Zvi,Yousef Al-Abed,Myoungsun Son

doi:10.3389/fimmu.2018.02824

Abstract

A primary mechanism for activation of innate immunity is recognition of damage or pathogen associated molecular patterns by pattern recognition receptors (PRRs). Nucleic acid is a damage associated molecular pattern molecule that when internalized into a monocyte and recognized by intracellular nucleic acid sensing toll like receptors will cause production of type 1 interferon. The process by which DNA or RNA is delivered into the cytosol of monocytes in systemic lupus erythematosus remains incompletely understood, and therapeutic approaches to prevent DNA-mediated monocyte activation are needed. We identified two mechanisms for internalization of DNA by monocytes. IgG-bound DNA was internalized by interacting with Fc gamma receptor IIa, while high-mobility group box-1 protein-bound DNA was internalized by interacting with the receptor for advanced glycation end products. Both pathways contribute to an inflammatory phenotype in monocytes exposed to serum from patients with SLE. Moreover, both of these pathways can be inhibited by a pentapeptide, DWEYS, which is a DNA mimetope. In one instance DWEYS directly competes with DNA for antibody binding and in the other DWEYS binds high-mobility group box-1 and blocks its interaction with RAGE. Our data highlight distinct pathways involved in nucleic acid enters monocytes in SLE, and identify a potential therapeutic to prevent nucleic acid internalization in SLE.

Highlights

Innate immunity, an evolutionarily conserved branch of the human immune system, employs pattern recognition receptors (PRRs) to recognize pathogen associated molecular patterns (PAMPs), molecules prevalent among bacteria and other microbes, and danger associated molecular patterns (DAMPs), self-molecules that are present at high concentration during tissue injury
Due to the technical challenges in measuring type 1 interferon levels, interferon stimulated genes (ISGs) expression often is used an as indicator of interferon activity
We incubated blood monocytes from healthy donors with control serum or serum from systemic lupus erythematosus (SLE) patients, and confirmed that healthy monocytes showed ISG upregulation when incubated with SLE serum consistent with increased tolllike receptors (TLRs) activation, whereas incubation of healthy monocytes with serum from control, healthy donors, did not exhibit ISG upregulation (Figure 1A)

Summary

Introduction

An evolutionarily conserved branch of the human immune system, employs pattern recognition receptors (PRRs) to recognize pathogen associated molecular patterns (PAMPs), molecules prevalent among bacteria and other microbes, and danger associated molecular patterns (DAMPs), self-molecules that are present at high concentration during tissue injury. PAMPs and DAMPs induce production of immune mediators such as proinflammatory. Because PRRs can be activated by host molecules, there are mechanisms to limit access of DAMPs to PRRs. For example, because the DNA sensing Toll-like receptor 9 (TLR9) has an endosomal location, circulating nucleic acid must be internalized to gain access to the endosome to mediate an inflammatory response. High-mobility group box-1 (HMGB1)-DNA complexes are internalized following interaction with the RAGE [1, 2] and IgG-DNA immune complexes (ICs) are internalized by Fc receptor engagement [3]. Serum levels of HMGB1 are low and IgG anti-DNA antibodies are not present, precluding the entry of extracellular DNA into cells and its transport to the endosomal compartment. While other mechanisms for cellular delivery of nucleic acid have been proposed [4, 5], their significance within the context of autoimmune disease is still not clear

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Conclusion