MCPIP3 orchestrates the balance of epidermal proliferation and differentiation.

Abstract

Background: Monocyte chemoattractant protein-induced protein 3 (MCPIP3), also called Regnase-3 and encoded by the ZC3H12C gene, is a member of the MCPIP family of RNases. Previous studies showed that MCPIP1 in keratinocytes plays a pivotal role in the maintenance of skin integrity and immunological function. Given that the expression of MCPIP3, similar to that of MCPIP1, is increased in psoriatic lesions compared with uninvolved skin, a role of MCPIP3 in the regulation of keratinocyte and epidermal biology was hypothesized.

Methods: This study aimed to investigate the specific function of the MCPIP3 protein in the skin. The expression pattern of MCPIP3 was studied in normal human epidermal keratinocytes (NHEKs) subjected to in vitro differentiation and upon stimulation with proinflammatory factors. Mice with keratinocyte-specific deletion of MCPIP3 (Mcpip3^loxP/loxPKrt14^Cre; MCPIP3^EKO) were generated and characterized. The response of the skin of MCPIP3^EKO mice to imiquimod (IMQ) and 12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated. The expression levels of key modulators of keratinocyte proliferation and differentiation were measured in MCPIP3^EKO model mice and in NHEKs transiently transfected with MCPIP3-specific siRNA. Reporter assays were used to identify direct targets of MCPIP3 nucleolytic activity.

Results: In human keratinocytes, the expression of ZC3H12C/MCPIP3 was rapidly induced by stimulation with TPA, IL-17a, IL-36α, and TNF-α. Although mice with keratinocyte-specific deletion of MCPIP3 (MCPIP3^EKO) did not develop skin inflammation, they displayed abnormalities in skin morphology. Stimulation with IMQ and TPA exacerbated epidermal hyperplasia caused by keratinocyte-specific deficiency of MCPIP3 and led to abnormal epidermal differentiation. The expression levels of keratinocyte proliferation and differentiation markers, such as keratin-14, cyclin B1, involucrin, and the S100 calcium-binding proteins S100A7/A9, were increased in NHEKs in which MCPIP3 expression was silenced. MCPIP3 negatively regulates the level of cyclin B1 mRNA via direct nucleolytic cleavage within its 3' untranslated region.

Conclusions: The MCPIP3 protein modulates the balance of keratinocyte proliferation and differentiation and functions as a regulator of epidermal morphology in vivo.