Neuroimmunologic cascades in the pathogenesis of psoriasis and psoriatic arthritis

Abstract

Psoriasis and its associated systemic inflammatory arthritis is a chronic inflammatory disease of unknown etiology. Significant progress has been made in elucidating the pathogenesis of psoriasis; still the molecular basis of the inflammatory and proliferative processes of psoriasis is largely unknown. The role of neurogenic inflammation has provided a new dimension in understanding the pathogenesis of various cutaneous and systemic inflammatory diseases such as atopic dermatitis, urticaria, rheumatoid arthritis, ulcerative colitis and bronchial asthma. In this article we have addressed certain key events with respect to the role of neurogenic inflammation in the development of a psoriatic lesion. Significant are the proliferation of nerves, upregulation of neuropeptides and increased levels of nerve growth factor (NGF). In immunoperoxidase studies, we found that keratinocytes in lesional and non-lesional psoriatic tissue express high levels of NGF in the terminal cutaneous nerves of psoriatic lesions and that there is a marked upregulation of the NGF receptors: p75 neurotrophin receptor (p75NTR) and tyrosine kinase A (TrkA). Keratinocytes of psoriatic plaques express increased levels of NGF and it is likely that murine nerves will promptly grow into the transplanted plaques on a severe combined immunodeficient (SCID) mouse. Indeed, we have noted marked proliferation of nerve fibers in transplanted psoriatic plaques on a SCID mouse compared with the few nerves seen in transplanted normal human skin. These observations, as well as a recent report suggesting therapeutic efficacy following manipulation of TrkA induced signal in the SCID-psoriasis xenograft model, further substantiate a contributing role of NGF and its receptor system in the pathogenesis of psoriasis. As psoriasis and psoriatic arthritis are within the spectrum of the same disease process, currently we are exploring the role of NGF/NGF-R in the pathophysiology of psoriatic arthritis. A new discipline has emerged in clinical pharmacology focusing on development of drugs targeting the neuropeptides (NP), NP receptors and the NGF/NGF-R system We are in the process of developing novel therapeutic agents for psoriasis and psoriatic arthritis by manipulating TrkA induced signal transductions. © 2009 Springer Berlin Heidelberg.