Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal dominant disorder associated with chronic itching and skin lichenification. In the lesional skin of FPLCA, amyloid materials on degenerated keratin filaments are deposited in upper dermis. The genetic basis of FPLCA involves mutations in the OSMR and IL31RA genes. OSMR beta encoded by the OSMR gene pairs with IL-31 receptor A encoded by the IL31RA gene to form the heterodimer receptor for IL-31. It is considered that the functional abnormality of these receptors caused by the mutations closely relates to pruritus of FPLCA. It has been reported that CCL2 expression is reduced in epidermis in FPLCA skin specimens, and that HaCaT cells stably transfected with a mutant IL31RA gene (p.S521F) showed both reduced STAT3 activation and impaired CCL2 expression. However, it is still unclear whether the reduced STAT3 activation and the impaired CCL2 expression are common and essential to other FPLCA cases, including those with OSMR gene mutations. It is also unclear whether pruritus is caused by the reduced STAT3 activation and/or the impaired CCL2 expression. In this study, we generated stably transfected HaCaT cell clones with the OSMR gene mutations, p.G618A and p.P694L, which were reported as causative mutations of FPLCA. Here we designate the generated cell clones, WT (for wild-type OSMR), G618A (for mutant OSMR-p.G618A), and P694L (for mutant OSMR-p.P694L), respectively. Interestingly, G618A and P694L showed clearly reduced CCL2 expression compared with WT and parental HaCaT cells. However, STAT3 in G618A and P694L were normally phosphorylated in response to OSM and IL-31 as well as that in WT and parental HaCaT cells . These results suggested that impaired CCL2 expression and abnormal signals in downstream of OSMR other than STAT3 in keratinocytes might be important in the pathogenesis of FPLCA.

Impaired CCL2 expression caused by the OSMR gene mutations in familial primary localized cutaneous amyloidosis