Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity

Martin, Stefan F.; Dudda, Jan C.; Bachtanian, Eva; Lembo, Annalisa; Liller, Stefanie; Dürr, Christoph; Heimesaat, Markus M.; Bereswill, Stefan; Fejér, György; Vassileva, Ralitsa; Jakob, Thilo; Freudenberg, Nikolaus; Termeer, Christian; Johner, Caroline; Galanos, Chris; Freudenberg, Marina A.

doi:10.1084/jem.20070509

Cited by 193 publications

(220 citation statements)

References 66 publications

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“…As an in vitro model for inducing p38α activity and p38α-dependent gene expression, we used Pam 3 CSK 4 , an agonist of Toll-like receptor 2 (TLR2), as a stimulant because it strongly induced p38α phosphorylation in DCs, and TLR2 signaling has been shown to be relevant to and crucial for CH (17,18). TLR2-activated p38α-KO DCs underwent functional maturation, gaining the ability to present a peptide antigen to and induce the proliferation of CD4 + and CD8 + T cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease

Ritprajak

Hayakawa²,

Sano³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The kinase p38α, originally identified because of its endotoxinand cytokine-inducible activity and affinity for antiinflammatory compounds, has been posited as a promising therapeutic target for various immune-mediated disorders. In clinical trials, however, p38α inhibitors produced adverse skin reactions and other toxic effects that often outweighed their benefits. Such toxicity may arise from a perturbation of physiological functions unrelated to or even protective against the disease being treated. Here, we show that the effect of interfering with p38α signaling can be therapeutic or adverse depending on the targeted cell type. Using a panel of mutant mice devoid of p38α in distinct cell types and an experimental model of allergic skin disease, we find that dendritic cell (DC)-intrinsic p38α function is crucial for both antigen-specific T-cell priming and T-cell-mediated skin inflammation, two independent processes essential for the immunopathogenesis. By contrast, p38α in other cell types serves to prevent excessive inflammation or maintain naïve T-cell pools in the peripheral lymphoid tissues. These findings highlight a dilemma in the clinical use of p38α inhibitors, yet also suggest cell-selective targeting as a potential solution for improving their therapeutic index.allergic contact dermatitis | contact hypersensitivity | hapten T he kinase p38α, the most abundant and ubiquitously expressed p38 MAP kinase isoform in mammals, was discovered based on its binding affinity for antiinflammatory compounds (1). The nature of the stimuli that elicited p38α activation and enabled its identification-proinflammatory cytokines, microbial products, and injurious environmental insultsalso hinted at a role for p38α in the immune and stress response (2-4). Pharmacological inhibition of p38α has since held promise for the treatment of allergic, autoimmune, and other diseases of inflammatory etiology. A series of recent clinical studies, however, revealed the frequent occurrence of adverse events, ranging from skin rashes to liver damage, after the use of p38α inhibitors (5-7). These toxicities limited the dose and frequency of p38α inhibitor treatment and have become a liability to fulfilling its promise as an effective therapeutic strategy.The therapeutic index is a relative measure of the efficacy versus toxicity of a treatment regimen. Toxic side effects have often been the cause of the failure of an otherwise effective therapeutic agent such as p38α inhibitors. We questioned whether the adverse effects of p38α inhibitors arose from interference with a physiological function of the protein kinase and, if so, whether the therapeutic and the adverse effects of p38α inhibition were based on distinct cell type-specific mechanisms. In this study, we used a mouse model of allergic contact dermatitis to examine the disease responses of conditional p38α knockout (KO) mice. In these mice, ablation of p38α expression was targeted to keratinocytes, myeloid cells, dendritic cells, or T cells, which represented a simulation of p38...

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Section: Resultsmentioning

confidence: 99%

Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease

Ritprajak

Hayakawa²,

Sano³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Skin infections occur more frequently in atopic dermatitis than in psoriasis. (14) TLR might contribute to the disordered immune activity in atopic dermatitis (15)(16)(17) and contact dermatitis (18,19). Data about TLR expression in atopic and contact dermatitis are lacking.…”

mentioning

confidence: 99%

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

Panzer

Blobel

Fölster‐Holst

et al. 2014

Experimental Dermatology

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The aim of the study was to investigate the expression of Toll-like receptors (TLRs) 2 and 4 on keratinocytes in atopic dermatitis, contact dermatitis, and psoriasis by PCR and by immunohistochemistry including confocal microscopy. Confocal microscopy revealed a granular intra-cellular expression pattern for TLR 2 and a homogenous intra-cellular expression pattern for TLR 4 in normal and diseased skin. TLR 2 was constitutively expressed in the suprabasal layers in normal skin, but limited to the basal epidermis in diseased skin. TLR 4 expression was concentrated to the basal layers in normal skin, whereas it was pronounced in upper layers in diseased skin. The shift in the TLR expression may be related to the disturbed skin barrier and a need for enhanced immune surveillance because of invading microbes. Also, there must be a balance between sufficient immune response and overstimulation.Abbreviation: TLR, Toll-like receptor.

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“…Specifically, interaction of low molecular weight hyaluronic acid (HA), a product of ECM breakdown, with TLR2 and TLR4, has recently been described. Notably, inhibition of HA using an HA inhibitor significantly abrogated the development of skin sensitization to TNCB (Martin et al, 2008). Additionally, there is evidence that suggests biglycan, another ECM breakdown product, is also capable of interacting with the TLR2 and TLR4 receptors (Schaefer et al, 2005).…”

Section: Toll Like Receptorsmentioning

confidence: 99%

Danger, intracellular signaling, and the orchestration of dendritic cell function in skin sensitization

Ainscough

Gerberick

Dearman

et al. 2012

Journal of Immunotoxicology

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Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity

Cited by 193 publications

References 66 publications

Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease

Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

Danger, intracellular signaling, and the orchestration of dendritic cell function in skin sensitization

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