A recent study, published in the journal Immunity, has uncovered a significant biological pathway that drives inflammation in psoriasis, a chronic skin condition characterized by red, flaky, and itchy lesions. The findings of this research conducted by experts from NYU Langone Health suggest potential implications for the treatment of various inflammatory skin diseases, such as atopic dermatitis, allergic dermatitis, and hidradenitis suppurativa.
Inflammation, the body’s natural response to irritation and infection, can manifest severely in conditions like psoriasis, leading to discomfort and skin damage. The study reveals that the interleukin-17 (IL-17) pathway, known for its role in inflammation and targeted by existing anti-inflammatory drugs, plays a crucial role in activating a protein called hypoxia inducible factor 1-alpha (HIF-1-alpha) in psoriasis. While IL-17’s involvement in inflammation has been recognized, the study sheds new light on the significance of HIF-1-alpha in this process.
Researchers observed that HIF-1-alpha enhances the metabolic activity of inflamed skin cells, promoting the breakdown of sugar for energy production and resulting in the generation of lactate, a waste product. Interestingly, lactate consumption by inflammatory T cells triggers the production of more IL-17, fueling a cycle of inflammation.
Analysis of human skin tissue samples from psoriasis patients revealed similarities in gene activity around IL-17 and HIF-1-alpha, indicating their interconnectedness. In experiments involving mice with induced psoriasis-like symptoms, treatment with an experimental drug inhibiting HIF-1-alpha effectively resolved inflammatory skin lesions.
Furthermore, skin samples from psoriasis patients treated with an anti-inflammatory drug showed reduced activity in both IL-17 and HIF-1-alpha, suggesting a correlation between the two. Additional experiments demonstrated that targeting HIF-1-alpha had a more pronounced effect on inflammatory gene activity compared to standard topical treatments.
Moreover, genetic analysis revealed decreased HIF-1-alpha activity in psoriasis patients treated with IL-17A-blocking drugs, highlighting the interdependence between IL-17 and HIF-1-alpha. In animal studies, inhibiting glucose metabolism in the skin slowed disease progression, suggesting a potential therapeutic strategy.
The researchers also investigated the role of lactate in psoriasis, finding that targeting lactate production or its uptake by immune cells could slow disease progression. These findings open avenues for developing novel therapies targeting HIF-1-alpha and lactate metabolism to alleviate inflammation in skin diseases.
Dr. Shruti Naik, corresponding author of the study, emphasized that while current therapies alleviate symptoms, they do not cure psoriasis. Further research is needed to refine experimental drugs targeting HIF-1-alpha before clinical trials can commence. Dr. Naik and her colleagues have a pending patent application for inflammatory skin disease therapies based on their work on HIF-1-alpha inhibition.
Psoriatic disease affects millions worldwide, underscoring the importance of advancing understanding and treatment of this condition. The research team intends to develop experimental drugs to disrupt the IL-17-driven inflammation cycle, potentially offering new hope for patients with psoriasis and related skin diseases.
