Abstract
Interleukin-31 (IL-31) is involved in excessive development of cutaneous sensory nerves in atopic dermatitis (AD), leading to severe pruritus. We previously reported that PQA-18, a prenylated quinolinecarboxylic acid (PQA) derivative, is an immunosuppressant with inhibition of p21-activated kinase 2 (PAK2) and improves skin lesions in Nc/Nga mice as an AD model. In the present study, we investigate the effect of PQA-18 on sensory nerves in lesional skin. PQA-18 alleviates cutaneous nerve fiber density in the skin of Nc/Nga mice. PQA-18 also inhibits IL-31-induced sensory nerve fiber outgrowth in dorsal root ganglion cultures. Signaling analysis reveals that PQA-18 suppresses phosphorylation of PAK2, Janus kinase 2, and signal transducer and activator of transcription 3 (STAT3), activated by IL-31 receptor (IL-31R), resulting in inhibition of neurite outgrowth in Neuro2A cells. Gene silencing analysis for PAK2 confirms the requirement for STAT3 phosphorylation and neurite outgrowth elicited by IL-31R activation. LC/MS/MS analysis reveals that PQA-18 prevents the formation of PAK2 activation complexes induced by IL-31R activation. These results suggest that PQA-18 inhibits the IL-31 pathway through suppressing PAK2 activity, which suppresses sensory nerve outgrowth. PQA-18 may be a valuable lead for the development of a novel drug for pruritus of AD.
Highlights
Atopic dermatitis (AD) is known as chronic inflammatory dermatitis with severe pruritus [1,2,3]
MO); rabbit anti-phosphoSTAT3 (Tyr705) (#9145) monoclonal antibody (mAb), rabbit anti-signal transducer and activator of transcription 3 (STAT3) (#12640) mAb, rabbit anti-phospho-JAK2 (Tyr1008) (#8082) mAb, rabbit anti-JAK2 (#3230) mAb, rabbit anti-p21-activated kinase 2 (PAK2) (#2608) polyclonal antibody, rabbit anti-phospho-PAK2 (Ser141) (#2606) polyclonal antibody were obtained from Cell Signaling Technology (Beverly, MA); Rabbit anti-PGP9.5 (NE1013) polyclonal antibody was obtained from Merck Millipore (Billerica, MA); Rabbit anti-IL-31Rα polyclonal antibody and rabbit anti-PAK-interacting exchange factor alpha (α-PIX) mAb were obtained from Abcam (Cambridge, MA); Recombinant mouse IL-31 protein (#210–31) was obtained from PeproTech (Rocky Hill, NJ); FRAX597 was obtained from Cayman Chemical (Ann Arbor, MI)
Treatment with anti-IL-31Rα antibody significantly increased PAK2 interaction with α-PIX, while that increase was significantly inhibited by treatment with prenylated quinolinecarboxylic acid (PQA)-18 (Fig 8B). These results suggest that PQA-18 inhibits IL-31-induced PAK2 activation through preventing formation of the PAK2 activation complex with GIT2 and α-PIX
Summary
Atopic dermatitis (AD) is known as chronic inflammatory dermatitis with severe pruritus [1,2,3]. Pruritus often causes scratching behavior, leading to disturbance of sleep and exacerbation of AD [4,5]. Since pruritus reduces the quality of life of AD patients, and the intensity of pruritus negatively correlates with psychosocial well-being, suppression of pruritus plays an important role in the improvement of AD [5,6]. It has been reported that most pruritus in AD is not suppressed by antihistamines [5,7], and the pruritus leads to the prolongation of AD treatment and the occurrence of side effects due to long-term administration [5,7,8]. The underlying mechanism of pruritus development in AD is not fully understood, recent
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