Prenylated quinolinecarboxylic acid compound-18 prevents sensory nerve fiber outgrowth through inhibition of the interleukin-31 pathway

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.

Post-Translational Modifications in Atopic Dermatitis: Current Research and Clinical Relevance

“…MAPKs play facilitatory roles in the susceptibility to inflammation, which could activate the TNF-α signaling cascades and energize the NF-κB signaling pathways ( Giridharan and Srinivasan, 2018 ); in turn, inflammatory cytokines could promote MAPK phosphorylation and aggravate the secretion of those mediators in AD development ( Hong et al, 2015 ; Ryu et al, 2015 ; Noh et al, 2016 ; Pinto et al, 2018 ; Naruke et al, 2021 ; Ogura et al, 2021 ). Specifically, higher FcεRI (a receptor of IgE, can be upregulated by p38 phosphorylation) is detected in peripheral blood monocytes of AD patients compared with normal individuals, which increases the susceptibility of microbial antigens and allergens ( Song et al, 2015 ).…”