The Oxidative Burst Mediates Anti-Inflammatory Clearance of Dead Cells in a Mouse Model of SLE and Inflammatory Arthritis

Jonas Hahn¹, Deborah Kienhöfer¹, Luis Munoz¹, Martin Herrmann², Gerhard Krönke³, Rikard Holmdahl⁴, Georg Schett⁵ and Markus Hoffmann¹, ¹Medicine III, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, ²Medicine III, Rheumatology and Immunology, University of Erlangen-Nuremberg, Osterreich, Germany, ³Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, ⁴Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden, ⁵Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Lupus and mouse model

Session Information

Date: Monday, November 9, 2015

Title: Systemic Lupus Erythematosus - Animal Models Poster I

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

The production of reactive oxygen species (ROS) via the oxidative burst has recently been implicated in regulation of inflammation and protection from arthritis, multiple sclerosis, and psoriasis. The aim of this project was to elucidate the impact of the oxidative burst on lupus-like autoimmunity.

Methods:

The clinical course of pristane-induced lupus (PIL) was compared between WT and ROS-deficient (Ncf1**) mice by analysis of serological markers and organ involvement. Ex vivophagocytosis assays and flow cytometry were employed to analyze uptake and degradation of cell debris. Formation of neutrophil extracellular traps (NETs) was monitored in blood and peritonea. Involvement of the antioxidative response was investigated by qPCR and ChIP.

Results:

Ncf1** mice developed strongly elevated levels of typical lupus-autoantibodies, e.g., anti-dsDNA, anti-histone and anti-Sm/RNP, arthritis, and glomerulonephritis resulting in earlier death. The enhanced inflammation also gives rise to higher serum levels of pro-inflammatory cytokines. Mice with a specific ROS-deficiency in neutrophil granulocytes exhibited an intermediate phenotype. We observed a preferential uptake of dead cell material but not of inert latex beads into inflammatory monocytes and granulocytes, and a dramatically reduced ability to forms NETs in Ncf1** mice. A similar phagocytosis phenotype was observed in patients with SLE. Immunoglobulin G-coating of latex beads significantly enhanced their uptake. Genes related to the antioxidative response dependent on the transcription factor NRF2 were strongly downregulated in Ncf1** mice.

Conclusion:

Our results show that autoimmunity occurring in the ROS-deficient Ncf1** mouse gives rise to exacerbated Rupus. Aberrant phagocytosis in ROS-deficient animals caused by spontaneously occurring autoantibodies to surface molecules of dead cells and a defective regulatory antioxidative response contribute to this phenotype.

Disclosure: J. Hahn, None; D. Kienhöfer, None; L. Munoz, None; M. Herrmann, None; G. Krönke, None; R. Holmdahl, None; G. Schett, None; M. Hoffmann, None.

To cite this abstract in AMA style:

Hahn J, Kienhöfer D, Munoz L, Herrmann M, Krönke G, Holmdahl R, Schett G, Hoffmann M. The Oxidative Burst Mediates Anti-Inflammatory Clearance of Dead Cells in a Mouse Model of SLE and Inflammatory Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/the-oxidative-burst-mediates-anti-inflammatory-clearance-of-dead-cells-in-a-mouse-model-of-sle-and-inflammatory-arthritis/. Accessed .

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