Mechanisms linking innate immunity and autoimmune responses are poorly understood1. Myeloid-related protein-8 (Mrp8) and Mrp14 are damage-associated molecular pattern molecules (DAMPs) highly upregulated in various autoimmune disorders. We show in a mouse autoimmune model that local Mrp8 and Mrp14 production is essential for the induction of autoreactive CD8+ T cells and the development of systemic autoimmunity. This effect is mediated via Toll-like receptor 4 (TLR4) signaling leading to increased interleukin-17 (IL-17) expression. Notably, expression of Mrp8 and Mrp14 was upregulated in cutaneous lupus erythematosus, and stimulation of CD8+ T cells from individuals with lupus erythematosus with MRP proteins resulted in an upregulation of IL-17, suggesting a key role for MRP8 and MRP14 for the development of autoreactive lymphocytes during human autoimmunity as well. These results demonstrate a link between local expression of DAMP molecules and the development of systemic autoimmunity.
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We would like to thank H. Hinte and C. Solé for excellent technical assistance. This work was supported by the Interdisciplinary Center of Clinical Research grant Lo2/017/07 to K.L. and S.B. as well as grant Vo2/014/09 to T.V., by the German Cancer Society grant 107891 to K.L. and S.B., by the Federal Ministry of Education and Research, project AID-Net to J.R. and by the German Research Association grant Lo817/2-1 to K.L. and S.B.
The authors declare no competing financial interests.
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Loser, K., Vogl, T., Voskort, M. et al. The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells. Nat Med 16, 713–717 (2010). https://doi.org/10.1038/nm.2150
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