Role of NGF and neurogenic inflammation in the pathogenesis of psoriasis.
A contributing 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. Several critical observations, such as (i) psoriasis resolves at sites of anaesthesia, (ii) neuropeptides are upregulated, and (iii) there is a marked proliferation of terminal cutaneous nerves in psoriatic plaques, encouraged us to search for a mechanism of neural influence in inflammation and inflammatory diseases. In immunohistochemical studies, we found that keratinocytes in lesional and nonlesional psoriatic tissue express high levels of nerve growth factor (NGF) and that there is a marked upregulation of NGF receptors, p75 neurotrophin receptor (p75NTR) and tyrosine kinase A (TrkA), in the terminal cutaneous nerves of psoriatic lesions. As keratinocytes of psoriatic plaques express increased levels of NGF, it is likely that murine nerves will promptly proliferate into the transplanted plaques on a severe combined immunodeficient mouse. Indeed, we have noted marked proliferation of nerve fibers in transplanted psoriatic plaques compared with the few nerves in transplanted normal human skin. By double label immunofluorescence staining, we have further demonstrated that in these terminal cutaneous nerves there is a marked upregulation of neuropeptides, such as substance P and calcitonin gene-related protein. These observations, as well as recent findings about NGF-induced chemokine expression in keratinocytes, further substantiate a role of the NGF-p75NTR-TrkA system in the inflammatory process of psoriasis. Currently, we are evaluating antagonists to selected neuropeptides and NGF/receptors, with the expectation of identifying pharmacological agents to counter neurogenic inflammation in psoriasis.
Raychaudhuri
Siba P
SP
Psoriasis Research Institute, Stanford University School of Medicine, 510 Ashton Avenue, Palo Alto, CA 94306, USA. raysiba@aol.com
Raychaudhuri
Smriti K
SK
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007154:Immune System Diseases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020078:Neurogenic Inflammation / Q000209:etiology / Q000378:metabolism*; D015213:Neuroimmunomodulation; D011565:Psoriasis / Q000150:complications / Q000378:metabolism*
D020932:Nerve Growth Factor