Abstract
Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, TLR2 deficiency unexpectedly exacerbated psoriasiform skin inflammation. Importantly, messenger RNA (mRNA) levels of Foxp-3 and IL-10 in the lesional skin were significantly decreased in TLR2 KO mice compared with wild-type mice. Furthermore, flow cytometric analysis of the lymph nodes revealed that the frequency of regulatory T cells (Tregs) among CD4-positive cells was decreased. Notably, stimulation with Pam3CSK4 (TLR2/1 ligand) or Pam2CSK4 (TLR2/6 ligand) increased IL-10 production from Tregs and DCs and the proliferation of Tregs. Finally, adoptive transfer of Tregs from wild-type mice reduced imiquimod-induced skin inflammation in TLR2 KO mice. Taken together, our results suggest that TLR2 signaling directly enhances Treg proliferation and IL-10 production by Tregs and DCs, suppressing imiquimod-induced psoriasis-like skin inflammation. Enhancement of TLR2 signaling may be a new therapeutic strategy for psoriasis.
Highlights
Psoriasis is characterized by acanthosis with massive infiltration of dendritic cells (DCs), T cells, neutrophils and macrophages [1,2]
We investigated the possible roles of TLR2 in the development of psoriasis, using a mouse psoriasis model induced by imiquimod, a ligand for TLR7 [20]
We show here that TLR2 deficiency unexpectedly exacerbates psoriasis-like skin inflammation through a decrease in regulatory T cells (Tregs) and impaired IL-10 production by Tregs and DCs
Summary
Psoriasis is characterized by acanthosis with massive infiltration of dendritic cells (DCs), T cells, neutrophils and macrophages [1,2]. It is widely accepted that the pathophysiology of psoriasis is related to the activation and dysregulation of the innate and adaptive immune system [2]. Environmental factors activate the innate immune system, which contributes to the initiation and maintenance of autoimmune diseases such as psoriasis [3]. Plasmacytoid DCs, activated through complexes of the antimicrobial peptide LL-37 and DNA in a toll-like receptor (TLR) 9-dependent manner, induce a proinflammatory cytokine cascade [4]. Interferon-alpha expressed by activated plasmacytoid DCs is important in the early phase of psoriasis, further activating dermal DCs and triggering downstream T cell-mediated adaptive immunity [5]. TLRs function as important sensors of both innate and adaptive immune systems [9]. We show here that TLR2 deficiency unexpectedly exacerbates psoriasis-like skin inflammation through a decrease in regulatory T cells (Tregs) and impaired IL-10 production by Tregs and DCs
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