Neurogenic factor-induced Langerhans cell activation in diabetic mice with mechanical allodynia

Jacqueline R Dauch,Lucía A Luna-Wong,Hsinlin T Cheng,Zachary A Kelly,Brandon M Yanik,Diane E Bender,Wilson Hsieh

doi:10.1186/1742-2094-10-64

Jacqueline R Dauch, Lucía A Luna-Wong + Show 5 more

Open Access

https://doi.org/10.1186/1742-2094-10-64

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Abstract

BackgroundLangerhans cells (LCs) are antigen-presenting dendritic cells located in the skin. It has been reported that LC activation is associated with painful diabetic neuropathy (PDN); however, the mechanism of LC activation is still unclear.MethodsThe db/db mouse, a rodent model of PDN, was used to study the roles of LCs in the development of PDN in type 2 diabetes. Hind foot pads from db/db and control db/+ mice from 5 to 24 weeks of age (encompassing the period of mechanical allodynia development and its abatement) were collected and processed for immunohistochemistry studies. LCs were identified with immunohistochemistry using an antibody against CD207 (Langerin). The intraepidermal nerve fibers and subepidermal nerve plexus were identified by immunohistochemistry of protein gene product 9.5 (PGP 9.5) and tropomyosin-receptor kinase (Trk) A, the high affinity nerve growth factor receptor.ResultsCD207-positive LCs increased in the db/db mouse during the period of mechanical allodynia, from 8 to 10 weeks of age, in both the epidermis and subepidermal plexus. At 16 weeks of age, when mechanical allodynia diminishes, LC populations were reduced in the epidermis and subepidermal plexus. Epidermal LCs (ELCs) were positive for Trk A. Subepidermal LCs (SLCs) were positive for CD68, suggesting that they are immature LCs. Additionally, these SLCs were positive for the receptor of advanced glycation end products (RAGE) and were in direct contact with TNF-α-positive nerve fibers in the subepidermal nerve plexus during the period of mechanical allodynia. Intrathecal administration of SB203580, a p38 kinase inhibitor, significantly reduced mechanical allodynia, TNF-α expression in the subepidermal plexus, and increased both ELC and SLC populations during the period of mechanical allodynia.ConclusionsOur data support the hypothesis that increased LC populations in PDN are activated by p38-dependent neurogenic factors and may be involved in the pathogenesis of PDN.

Highlights

Langerhans cells (LCs) are antigen-presenting dendritic cells located in the skin
Our results provide evidence that inhibition of nerve growth factor (NGF)/p38 signaling in peripheral nerves could prevent LC-mediated immune activation in skin, and serve as a potential treatment for painful diabetic neuropathy (PDN)
CD207 immunohistochemistry detected LCs in the epidermal (ELCs, Figure 1, arrows) and the subepidermal plexus (SLCs, Figure 1, arrowheads). Increased numbers of both Epidermal langerhans cell (ELC) and Subepidermal langerhans cell (SLC) were detected in db/db mice compared to db/+ mice (Figure 1)

Summary

Introduction

It has been reported that LC activation is associated with painful diabetic neuropathy (PDN); the mechanism of LC activation is still unclear. Diabetic neuropathy (DN) is the most common diabetic complication that affects at least 50% of patients with either type 1 or type 2 diabetes [2,3]. At least 40% to 50% of patients with DN develop painful diabetic neuropathy (PDN), which presents as abnormal sensory symptoms including allodynia (increased sensitivity to innocuous stimuli), hyperalgesia (exaggerated response to noxious stimuli), and/or spontaneous pain [4,5]. There are multiple presentations of PDN in diabetic patients, the most common symptoms of PDN result from a lengthdependent polyneuropathy that is associated with damage of peripheral nerve endings in the skin [6]. Only less than 30% of patients obtain satisfactory pain relief [7]

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