Upregulation of TLR2 in keratinocytes activates the MAPK pathway and plays a role in the pathogenesis of hidradenitis suppurativa

Haini Zhang; Yi Li; Xiaodong Lai; Chong Zhang; Zhongshuai Wang; Yan Yang; Baoxi Wang; Yan Yan

doi:10.1016/j.jdermsci.2024.11.002

Upregulation of TLR2 in keratinocytes activates the MAPK pathway and plays a role in the pathogenesis of hidradenitis suppurativa

J Dermatol Sci. 2024 Nov 22:S0923-1811(24)00221-4. doi: 10.1016/j.jdermsci.2024.11.002. Online ahead of print.

Authors

Haini Zhang¹, Yi Li¹, Xiaodong Lai¹, Chong Zhang¹, Zhongshuai Wang¹, Yan Yang¹, Baoxi Wang², Yan Yan³

Affiliations

¹ Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: wangbaoxi@psh.pumc.edu.cn.
³ Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: yanyan@psh.pumc.edu.cn.

PMID: 39732613
DOI: 10.1016/j.jdermsci.2024.11.002

Abstract

Background: Mutations in gamma-secretase complex (GSC) genes are associated with hidradenitis suppurativa (HS), and toll-like receptor (TLR) 2 is elevated in HS lesions. However, it remains unclear whether TLR2 is upregulated in the skin lesions of patients with HS with GSC gene variants, and the role of its upregulation in the pathogenesis of this disease are unknown.

Objective: To investigate the role of TLR2 upregulation in NCSTN and PSENEN knockdown keratinocytes.

Methods: Human immortalized keratinocyte line (HaCaTs) was treated with potent short-hairpin RNA targeting NCSTN or PSENEN. RNA sequencing was used to assess the effects of PAM2CSK4 treatment on gene expression in HaCaT cells. Altered signaling pathways were confirmed in both HaCaT cells, as well as in skin lesions from patients with HS and in Ncstn keratinocyte-specific knockout (Ncstn^ΔKC) mice.

Results: TLR2 agonist stimulation exacerbated the increased phosphorylation levels of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase (MAPK) in NCSTN- and PSENEN- knockdown keratinocytes. Similar findings were observed in skin lesions from patients with HS and Ncstn^ΔKC mice.

Conclusion: Novel variations were identified within the GSC gene in Chinese patients with HS. Moreover, our study indicates that TLR2/MAPK signaling pathways play a key role in the pathogenesis of HS associated with GSC gene mutations and represent a crucial therapeutic target.

Keywords: GSC; MAPK pathway; TLR2; hidradenitis suppurativa.