The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells.
Mechanisms linking innate immunity and autoimmune responses are poorly understood. 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.
Loser
Karin
K
Department of Dermatology, University of Münster, Münster, Germany. loserk@uni-muenster.de
Vogl
Thomas
T
Voskort
Maik
M
Lueken
Aloys
A
Kupas
Verena
V
Nacken
Wolfgang
W
Klenner
Lars
L
Kuhn
Annegret
A
Foell
Dirk
D
Sorokin
Lydia
L
Luger
Thomas A
TA
Roth
Johannes
J
Beissert
Stefan
S
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology* / Q000502:physiology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D040501:Calgranulin A / Q000276:immunology* / Q000502:physiology; D040502:Calgranulin B / Q000276:immunology* / Q000502:physiology; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology / Q000502:physiology; D008178:Lupus Erythematosus, Cutaneous / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology / Q000502:physiology
D040501:Calgranulin A; D040502:Calgranulin B; D020381:Interleukin-17; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D023201:CD40 Ligand
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