Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

Abstract

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.

Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis

“…For IL-17 neutralization, mice were injected with 250μg of anti-IL-17A antibody (clone 17F3, BioXCell) in PBS starting at the same time as the first DT injection, then every 2 to 3 days until they were euthanized at 3 weeks. This dosing regime was based on previous publications (47). Control mice were injected with corresponding doses of polyclonal IgG from normal rat sera (Thermo Scientific).…”

The Interleukin-1 Family: Back to the Future

“…TIR8-deficiency is also associated with increased susceptibility to develop allergy and autoimmunity in various models including systemic lupus erythematosus, lupus nephritis, (Lech et al, 2008; Lech et al, 2010), arthritis (Drexler et al, 2010), experimental autoimmune encephalomyelitis, and psoriasis (Russell et al, 2013). In the latter cases, TIR8 dampens IL-1-dependent differentiation of Th17 and Tγδ17 cells (Gulen et al, 2010; Russell et al, 2013).…”

T cell responses in psoriasis and psoriatic arthritis

“…This unconventional T cells displaying less-198 specific antigen responses have been proposed to initiate and precede 199 the participation of Th17 cells in psoriasis. Mouse model of psoriasis-200 like skin inflammation induced by treatment with Toll-like receptor 201 (TLR)7/8 agonist imiquimod, has indeed indicated that innate rather 202 than adaptive immune responses is involved in the primary formation 203 of psoriatic skin lesions and showed the critical role of the IL-23/IL-17/ 204IL-22 axis for the psoriatic phenotype[38].205This finding adds a new important variable to the scenario of T cell 206 responses in psoriasis pathogenesis[39,40].207 As concerns psoriatic arthritis, association with natural killer cell 208 pathways has been reported, as the presence of some allotypes of the 209 killer cell immunoglobulin-like receptor (KIR) superfamily has been 210 found to influence disease susceptibility [22,41]. Indeed, it has been sug-211 gested that KIR expression in the synovial fluid of patients with psoriatic 212 arthritis is dominated by activating KIRs underlining the possibility to 213 evaluate the role of innate lymphoid cells in determining psoriatic 214 arthritis in parallel with the analysis of γδ T cells in the pathogenesis cells were considered to be the main mediators of 218 the immune response in psoriatic plaques, then in recent years, the 219 attention moved to the role of Th17 cells [42].220 Th17 cytokines, in particular interleukin IL-17A, have been shown to 221 be critical for sustaining inflammation in psoriatic plaques.…”