Session Information
Session Type: Poster Session (Tuesday)
Session Time: 9:00AM-11:00AM
Background/Purpose: A hallmark of lupus is the presence of antinuclear autoantibodies, including those against RNA-protein complexes and double-stranded DNA (dsDNA).1,2 FcγR-mediated internalization of these nucleic acid:autoantibody immune complexes results in endosomal activation of TLR7 and TLR9, respectively, and the production of IFNα from plasmacytoid dendritic cells (pDC).3,4 The importance of this pathway is underscored by the majority of systemic lupus erythematosus (SLE) patients having a peripheral interferon-stimulated gene (ISG) signature.5 IRAK4 is a serine/threonine kinase at the top of the signaling cascade downstream of TLRs, including TLR7 and TLR9. As such, inhibition of IRAK4 represents a promising therapeutic target for lupus. The objective of this study is to investigate the effect of a highly selective IRAK4 inhibitor on IFNα production from pDCs stimulated with TLR7 and TLR9 agonists, SLE serum, and nucleic acid:autoantibody immune complexes.
Methods:
Primary human pDCs were precultured with an IRAK4 inhibitor followed by stimulation for 24 hours. Stimulation agents included TLR7 and TLR9 agonists, human SLE serum, and nucleic acid:autoantibody immune complexes. Culture supernatants were then assessed for secretion of IFNα by MSD.
Results: TLR7 and TLR9 stimulation of pDCs resulted in the secretion of IFNα from pDCs as expected. Treatment with an IRAK4 inhibitor resulted in dose-dependent inhibition of TLR7- and TLR9-induced IFNα with high potency. Human SLE serum was tested to extend findings to physiological SLE-relevant stimuli. Several SLE serum samples, which had positive ELISA titers to the antinuclear antibodies, stimulated production of IFNα in pDCs after 24 hours in culture. No induction of IFNα was observed with healthy volunteer serum samples. Treatment with an IRAK4 inhibitor effectively blocked secretion of IFNα from SLE serum-stimulated pDCs in a dose-dependent manner. Additional antigen (either RNP or dsDNA) was added to SLE samples that yielded titers for autoantibodies but failed to elicit IFNα production. Addition of RNP or dsDNA to anti–RNP and anti–dsDNA-positive SLE sera induced strong IFNα production, and this response was blocked with IRAK4 inhibition. No induction was seen with SLE serum that was negative for both anti–RNP and anti–dsDNA.
Conclusion:
This work demonstrates the effects of IRAK4 inhibition on IFNα production in primary pDCs downstream of disease-relevant stimuli and highlights the potential for IRAK4 inhibition as a promising treatment for lupus.
References:
1. Rose T, Dorner T. Best Pract Res Clin Rheumatol. 2017;31:321-333.
2. Zharkova O, et al. Rheumatology. 2017;56:i55-i66.
3. Barrat FJ, et al. J Exp Med. 2005;202(8):1131-1139.
4. Means TK, et al. J Clin Invest. 2005;115(2):407-417.
5. Yao Y, et al. Hum Genomics Proteomics. 2009. 2009(374312):1-16.
To cite this abstract in AMA style:
Hammond A, Parghi S, Wright N, Grant E, Taylor J, Warr M. IRAK4 Inhibition Suppresses TLR7, TLR9, and SLE Serum-Induced IFNA Production in Primary Human Plasmacytoid Dendritic Cells [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/irak4-inhibition-suppresses-tlr7-tlr9-and-sle-serum-induced-ifna-production-in-primary-human-plasmacytoid-dendritic-cells/. Accessed .« Back to 2019 ACR/ARP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/irak4-inhibition-suppresses-tlr7-tlr9-and-sle-serum-induced-ifna-production-in-primary-human-plasmacytoid-dendritic-cells/