Targeting the epigenetic regulator bromodomain-containing protein 4 by BRD4 siRNA lipoplexes and PFI-1 in psoriasis
Sowjanya Thatikonda1, Venkatesh Pooladanda1, Geetanjali Devabattula1
1Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India.
Abstract:
Psoriasis is a chronic skin disease characterized by keratinocyte hyperproliferation, epidermal hyperplasia, and immune cell infiltration involving both innate and adaptive immune systems. Bromodomain-containing protein 4 (BRD4), part of the Bromodomain and Extra-Terminal (BET) family, is implicated in various inflammatory and hyperproliferative disorders, though its role in psoriasis is unclear. This study investigates BRD4's role in psoriasis pathogenesis using BRD4-specific small interfering RNA (siRNA) lipoplexes (BRD4-siRNA-LP) and the small molecule inhibitor PFI-1. BRD4's effect was analyzed in human macrophages through gene-specific knockout and overexpression. Transfection of pcDNA5-Flag-BRD4-WT in macrophages activated core inflammatory regulators, while BRD4 disruption via BRD4-siRNA and BRD4 p5188 pSUPER-shRNA inhibited inflammation-related gene transcription. Topical application of BRD4-siRNA-LP and PFI-1 on Imiquimod (IMQ)-treated mice significantly reduced psoriatic plaques and epidermal hyperplasia. BRD4 inhibition notably downregulated pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, TGF-β, and TNF-α. Both in vitro and in vivo findings showed that BRD4 suppression significantly decreased the expression of signaling proteins including p65 NF-κB, MAPKs, and STAT3. Furthermore, BRD4 was found to interact with p65 NF-κB and STAT3, and its inhibition disrupted these protein-protein interactions. Inhibiting BRD4 with BRD4-siRNA-LP and PFI-1 effectively alleviates experimental psoriasis symptoms, making it a promising target for therapeutic intervention in psoriasis.
Insights
Bromodomain-containing protein 4 (BRD4) inhibition effectively treats psoriasis symptoms in mice by reducing inflammation and skin thickening. This suggests BRD4 is a promising therapeutic target for psoriasis treatment.
Area of Science:
- Dermatology
- Molecular Biology
- Immunology
Background:
- Psoriasis is a chronic inflammatory skin condition involving keratinocyte hyperproliferation and immune cell infiltration.
- Bromodomain-containing protein 4 (BRD4), a BET family member, is linked to inflammatory disorders, but its role in psoriasis is not well understood.
Purpose of the Study:
- To investigate the role of BRD4 in psoriasis pathogenesis.
- To evaluate the therapeutic potential of BRD4 inhibition in experimental psoriasis.
Main Methods:
- Utilized BRD4-specific small interfering RNA lipoplexes (BRD4-siRNA-LP) and the small molecule inhibitor PFI-1.
- Analyzed BRD4's effects in human macrophages via gene knockout and overexpression.
- Assessed outcomes in Imiquimod (IMQ)-induced psoriasis mouse models.
Main Results:
- BRD4 inhibition downregulated pro-inflammatory cytokines (IL-1β, IL-6, IL-17, TGF-β, TNF-α) and key signaling proteins (p65 NF-κB, MAPKs, STAT3).
- BRD4 suppression reduced psoriatic plaque formation and epidermal hyperplasia in mice.
- BRD4 was found to interact with p65 NF-κB and STAT3, and inhibition disrupted these interactions.
Conclusions:
- BRD4 plays a significant role in psoriasis pathogenesis.
- Inhibiting BRD4 with BRD4-siRNA-LP and PFI-1 effectively alleviates experimental psoriasis.
- BRD4 represents a promising therapeutic target for psoriasis treatment.
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