Hydroxychloroquine exacerbates imiquimod-induced psoriasis-like dermatitis through stimulating overexpression of IL-6 in keratinocytes

Abstract

Objective

Hydroxychloroquine (HCQ) is a US Food and Drug Administration (FDA)-approved treatment for systemic lupus erythematosus (SLE) through inhibition of antigen presentation and subsequent reduction in T cell activation. Psoriasis relapse after antimalarial therapy have been reported in up to 18% of patients with psoriasis. Here, we explored the role of HCQ on exacerbating dermatitis utilizing an imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model.

Methods

Thirty-six C57BL/6 female mice were divided into six groups: wild-type control, IMQ-Only, pre-treat HCQ (30 mg/kg and 60 mg/kg HCQ), and co-treat HCQ with IMQ (30 mg/kg and 60 mg/kg HCQ). Besides control, all were topically treated with IMQ for 5 days. Pharmacological effects and mechanisms of HCQ were assessed by clinical severity of dermatitis, histopathology, and flow cytometry. HaCaT cells were co-treated with both HCQ and recombinant IL-17A, followed by the detection of proinflammatory cytokine expression and gene profiles through enzyme-linked immunosorbent assay and next-generation sequencing.

Results

In the pre-treated and co-treated HCQ groups, skin redness and scaling were significantly increased compared to the IMQ-Only group, and Th17 cell expression was also upregulated. Acanthosis and CD11b⁺IL23⁺ dendritic cell (DC) infiltration were observed in the HCQ treatment group. IL-6 overexpression was detected in both the HaCaT cells and skin from the experimental mice. Psoriasis-related genes were regulated after being co-treated with HCQ and recombinant IL-17A in HaCaT cells.

Conclusions

HCQ exacerbates psoriasis-like skin inflammation by increasing the expression of IL-6, stimulating DC infiltration, and promoting Th17 expression in the microenvironment of the skin.

Key messages

This study provided possible mechanisms for inducing psoriasis during HCQ treatment through an animal model.

Keywords:

• Hydroxychloroquine
• psoriasis
• imiquimod-induced psoriasis-like dermatitis mouse model

Statements and declarations

Competing interests

The authors have no relevant financial or nonfinancial interests to disclose.

Author contributions

All authors contributed to the study conception and design. SJY and YCC performed material preparation and data collection and analyzed experiments. LJY, YCC, KCW, MSC, and CLL analyzed experiments and provided reagent and technique support. LJY, YCC, LYL, and SJY wrote the first draft of the manuscript, and all authors contributed to the development of the manuscript, including interpretation of results, substantive review of drafts and approval of the final draft for submission. Dr LYL and Dr SJY accepted full responsibility for the finished work and the conduct of the study, had access to the data, and controlled the decision to publish.

Ethical approval information, institution(s) and number(s)

All animal experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of Kaohsiung Veterans General Hospital (IACUC-2207-2212-2203).

Patient and public involvement

Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review

Not commissioned; externally peer reviewed.

Data availability statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Additional information

Funding

This study was supported by grants from the Kaohsiung Veterans General Hospital (KSVGH110-069), the Taichung Veterans General Hospital (TCVGH1127318C), and the National Science and Technology Council (NSTC 112-2314-B-075B-018).