Cutaneous Denervation of Psoriasiform Mouse Skin Improves Acanthosis and Inflammation in a Sensory Neuropeptide-Dependent Manner

Abstract

Nervous system involvement in psoriasis pathogenesis is supported by increases in nerve fiber numbers and neuropeptides in psoriatic skin and by reports detailing spontaneous plaque remission following nerve injury. Using the KC-Tie2 psoriasisform mouse model, we investigated the mechanisms by which nerve injury leads to inflammatory skin disease remission. Cutaneous nerves innervating dorsal skin of KC-Tie2 animals were surgically axotomized and beginning 1d following denervation, CD11c+ cell numbers decreased by 40% followed by a 30% improvement in acanthosis at 7d and a 30% decrease in CD4+ T cell numbers by 10d. Restoration of SP signaling in denervated KC-Tie2 skin prevented decreases in CD11c+ and CD4+ cells but had no affect on acanthosis; restoration of CGRP signaling reversed the improvement in acanthosis and prevented denervated-mediated decreases in CD4+ cells. Under innervated conditions, small molecule inhibition of SP in KC-Tie2 animals resulted in similar decreases to those observed following surgical denervation for cutaneous CD11c+ and CD4+ cell numbers; whereas small molecule inhibition of CGRP resulted in significant reductions in CD4+ cell numbers and acanthosis. These data demonstrate that sensory nerve-derived peptides mediate psoriasiform dendritic cell and T cell infiltration and acanthosis and introduce targeting nerve-immunocyte/keratinocyte interactions as potential psoriasis therapeutic treatment strategies.

Crosstalk between the nociceptive and immune systems in host defence and disease

“…These data are in agreement with a previous study in which surgical denervation improved skin lesions and inflammation in a mouse model of psoriasis (KC-Tie2). Importantly, a role for SP and CGRP signalling was also suggested in this work 149 . Interestingly, clinical reports show that psoriasis undergoes remission following nerve transection or injury in the context of decreased functioning of the nervous system, a finding that has also been observed in rodent models of the condition [149][150][151] .…”

The Regulation of Immunological Processes by Peripheral Neurons in Homeostasis and Disease

“…In a genetic mouse model of chronic psoriasiform dermatitis accompanied by enhanced cutaneous innervation, Ward and colleagues showed that surgical denervation ameliorated epidermal hyperplasia and some inflammatory parameters [191]. In this model, Substance P promoted the accumulation of CD11c + leukocytes, CGRP was important for epidermal thickening, and blockade of neuropeptide release by local injection of botulinum neurotoxin could ameliorate disease [191, 192]. …”

Calcitonin gene‐related peptide: key regulator of cutaneous immunity

“…In one model, mice are engineered to overexpress the receptor tyrosine kinase Tie2 in keratinocytes (Wolfram et al . 2009, Ostrowski et al . 2011).…”