Small Interfering RNA Targeting of Keratin 17 Reduces Inflammation in Imiquimod-Induced Psoriasis-Like Dermatitis

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Small Interfering RNA Targeting of Keratin 17 Reduces Inflammation in Imiquimod-Induced Psoriasis-Like Dermatitis

Psoriasis is a chronic autoimmune skin disease characterized by red, scaly plaques that significantly impact patients’ quality of life. Despite extensive research, the exact pathogenesis of psoriasis remains unclear, and current treatments are often insufficient. This study investigates the therapeutic potential of targeting keratin 17 (K17) using small interfering RNA (siRNA) in a mouse model of imiquimod (IMQ)-induced psoriasis-like dermatitis.

Introduction Psoriasis affects 2-3% of the global population, causing substantial physical and psychological burdens. The disease involves complex interactions between genetic and environmental factors, leading to abnormal keratinocyte proliferation and differentiation. Both innate and adaptive immune systems play crucial roles in the dysregulated immune responses observed in psoriasis. Current treatments are limited in efficacy, highlighting the need for novel therapeutic approaches.

Keratin 17 (K17), a type I intermediate filament, is overexpressed in psoriatic epidermis and has been implicated in the disease’s pathogenesis. K17 not only provides structural support but also interacts with immune cells, particularly T cells, contributing to the inflammatory response in psoriasis. This study explores the hypothesis that inhibiting K17 expression through siRNA could alleviate psoriasis symptoms.

Methods The study utilized eight-week-old female BALB/c mice to establish an IMQ-induced psoriasis-like dermatitis model. Mice were treated with a 5% IMQ cream on both ears daily for ten days. On day three, K17-specific siRNA was applied topically to the left ears, while the right ears received negative control (NC) siRNA. Two specific K17 siRNAs (K17 siRNA1 and K17 siRNA2) were used individually and in combination (siRNA Mix).

Inflammation was assessed through various methods:

  1. Gross ear thickness measurements using a microcaliper
  2. Histopathological analysis of hematoxylin and eosin (H&E)-stained ear sections
  3. Immunofluorescence to detect inflammatory cell infiltration (CD3+ T cells and Ly6G+ neutrophils)
  4. Real-time quantitative polymerase chain reaction (RT-qPCR) to measure cytokine and chemokine expression levels

Statistical analysis was performed using unpaired t-tests and one-way analysis of variance, with P < 0.05 considered statistically significant.

Results The study demonstrated significant improvements in psoriasis-like symptoms following K17 siRNA treatment:

  1. Phenotypic Improvement: Mice treated with K17 siRNA showed reduced erythema and scaling compared to NC siRNA-treated mice.
  2. K17 Expression: K17 siRNA effectively reduced K17 expression by more than 50% in treated ears (P < 0.05 vs. NC siRNA).
  3. Ear Thickness: K17 siRNA treatment significantly decreased ear thickness from day 6 to day 10 (P < 0.05 vs. NC siRNA).
  4. Histopathology: K17 siRNA-treated ears showed reduced inflammatory cell infiltration and epidermal hyperplasia compared to controls.
  5. Keratinocyte Markers: K17 siRNA treatment increased expression of differentiation markers K1 and K10 while decreasing proliferation marker K16.
  6. Inflammatory Cells: Treatment reduced infiltration of CD3+ T cells and Ly6G+ neutrophils in psoriatic lesions.
  7. Cytokine Expression: K17 siRNA decreased expression of pro-inflammatory cytokines (IL-17, IL-22, IL-23) and chemokines (CXCL1, CCL20).

Discussion The findings support the hypothesis that K17 plays a crucial role in psoriasis pathogenesis and that targeting K17 through siRNA can effectively alleviate psoriatic inflammation. The results align with the proposed K17/T cell/cytokine positive feedback regulatory loop in psoriasis, where K17 links aberrant keratinocyte proliferation with the production of psoriatic-related cytokines.

The study’s success in using topical siRNA delivery is particularly noteworthy. By combining liposomes (Lipofectamine 3000) with an emulsion matrix, the researchers achieved effective siRNA delivery to the skin. This approach offers potential advantages over systemic treatments, including reduced likelihood of systemic toxicity and more targeted action.

The observed reduction in inflammatory cell infiltration and cytokine production following K17 siRNA treatment suggests that K17 not only affects keratinocyte behavior but also modulates immune responses in psoriasis. The decrease in chemokine expression (CXCL1 and CCL20) may explain the reduced recruitment of neutrophils and dendritic cells to psoriatic lesions.

The study’s findings have several important implications:

  1. K17 as a Therapeutic Target: The results reinforce K17’s potential as a therapeutic target in psoriasis treatment.
  2. RNAi Therapy: The success of siRNA treatment opens possibilities for RNA interference-based therapies in dermatological conditions.
  3. Topical Delivery: The effective use of topical siRNA delivery suggests a promising route for localized treatment of skin disorders.
  4. Combination Therapy: The comparable efficacy of individual and combined siRNA treatments provides flexibility in therapeutic approaches.

Future Directions While the study demonstrates promising results, several areas warrant further investigation:

  1. Long-term Effects: Studies examining the durability of K17 siRNA treatment and potential for disease recurrence.
  2. Combination Therapies: Exploration of K17 siRNA in combination with existing psoriasis treatments.
  3. Human Studies: Translation of findings to human clinical trials to assess safety and efficacy in patients.
  4. Mechanism Elucidation: Further investigation into the precise mechanisms by which K17 siRNA modulates immune responses in psoriasis.
  5. Delivery Optimization: Development of more efficient and stable siRNA delivery systems for topical application.

Conclusion This study provides compelling evidence that K17 plays a critical role in psoriasis pathogenesis and that targeting K17 through siRNA can significantly alleviate psoriatic inflammation. The findings suggest that K17 siRNA therapy, particularly through topical application, could become a valuable addition to the psoriasis treatment arsenal. As research progresses, K17-targeted therapies may offer new hope for patients suffering from this chronic and often debilitating condition.

doi.org/10.1097/CM9.0000000000001197

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