Abstract
BackgroundAlthough the activation of dermal dendritic cells (DCs) or Langerhans cells (LCs) via p38 mitogen-activated protein kinase (MAPK) plays a crucial role in the pathogenesis of metal allergy, the in vivo molecular mechanisms have not been identified and a possible therapeutic strategy using the control of dermal DCs or LCs has not been established. In this study, we focused on dermal DCs to define the in vivo mechanisms of metal allergy pathogenesis in a mouse nickel (Ni) allergy model. The effects of DC therapy on Ni allergic responses were also investigated.Methods and FindingThe activation of dermal DCs via p38 MAPK triggered a T cell-mediated allergic immune response in this model. In the MAPK signaling cascade in DCs, Ni potently phosphorylated MAP kinase kinase 6 (MKK6) following increased DC activation. Ni-stimulated DCs could prime T cell activation to induce Ni allergy. Interestingly, when MKK6 gene-transfected DCs were transferred into the model mice, a more pronounced allergic reaction was observed. In addition, injection of short interfering (si) RNA targeting the MKK6 gene protected against a hypersensitivity reaction after Ni immunization. The cooperative action between T cell activation and MKK6-mediated DC activation by Ni played an important role in the development of Ni allergy.ConclusionsDC activation by Ni played an important role in the development of Ni allergy. Manipulating the MKK6 gene in DCs may be a good therapeutic strategy for dermal Ni allergy.
Highlights
dendritic cells (DCs) activation by Ni played an important role in the development of Ni allergy
Metal allergy is an inflammatory disease categorized as a delayed-type hypersensitivity (DTH) reaction, similar to contact dermatitis and eczema [1,2]
There is no evidence that DCs or Langerhans cells (LCs) can directly clear Ni, these antigen-presenting cells (APCs) may contribute to a Ni allergic response via other molecular mechanisms
Summary
Metal allergy is an inflammatory disease categorized as a delayed-type hypersensitivity (DTH) reaction, similar to contact dermatitis and eczema [1,2] This skin disease is induced by a complex process involving immune responses of numerous cell types, and cooperation among these cells is crucial for symptom development [3,4]. Langerhans cells (LCs) or dermal dendritic cells (DCs) play fundamental roles as APCs for uptake, processing, and presentation of antigens [11,12]. The activation of dermal dendritic cells (DCs) or Langerhans cells (LCs) via p38 mitogen-activated protein kinase (MAPK) plays a crucial role in the pathogenesis of metal allergy, the in vivo molecular mechanisms have not been identified and a possible therapeutic strategy using the control of dermal DCs or LCs has not been established. The effects of DC therapy on Ni allergic responses were investigated
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