Toll IL-1R8/single Ig IL-1-related receptor regulates psoriasiform inflammation through direct inhibition of innate IL-17A expression by γδ T cells

Expression of the orphan receptor Toll IL-1R8/single Ig IL-1-related receptor has been reported to be reduced in the peripheral blood of psoriatic arthritis patients. However whether TIR8/SIGIRR activity plays a specific role in regulating psoriatic inflammation is unknown. We report that Tir8/Sigir...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2013-09, Vol.191 (6), p.3337-3346
Main Authors: Russell, Shane E, Stefanska, Anna M, Kubica, Malgorzata, Horan, Rachel M, Mantovani, Alberto, Garlanda, Cecilia, Fallon, Padraic G, Walsh, Patrick T
Format: Article
Language:English
Subjects:
Animals
Arthritis, Psoriatic - immunology
Arthritis, Psoriatic - metabolism
Arthritis, Psoriatic - pathology
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Inflammation - immunology
Inflammation - metabolism
Inflammation - pathology
Interleukin-17 - biosynthesis
Interleukin-17 - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Real-Time Polymerase Chain Reaction
Receptors, Antigen, T-Cell, gamma-delta - immunology
Receptors, Antigen, T-Cell, gamma-delta - metabolism
Receptors, Interleukin-1 - immunology
Receptors, Interleukin-1 - metabolism
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
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Summary:Expression of the orphan receptor Toll IL-1R8/single Ig IL-1-related receptor has been reported to be reduced in the peripheral blood of psoriatic arthritis patients. However whether TIR8/SIGIRR activity plays a specific role in regulating psoriatic inflammation is unknown. We report that Tir8/Sigirr-deficient mice develop more severe psoriatic inflammation in both the chemical (Aldara)- and cytokine (rIL-23)-induced models of psoriasis. Increased disease severity was associated with enhanced infiltration of Vγ4⁺ γδ T cells that express significantly elevated levels of IL-17A. Critically, we also demonstrate that TIR8/SIGIRR activity directly suppressed innate IL-17A expression by γδ T cells in vitro and in vivo. Importantly, treatment of Tir8/Sigirr⁻/⁻ mice with an IL-17A neutralization Ab reversed the enhanced disease severity observed in these mice. This study identifies TIR8/SIGIRR as a novel intrinsic negative regulator of innate IL-17A expression and characterizes a novel mechanism involved in the regulation of psoriatic inflammation.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1300828