Abstract
Psoriasis is a complex autoimmune disease characterized by dysregulated interactions between keratinocytes and immune cells. Over the past decade, various antimicrobial peptides, chemokines, and cytokines have been discovered as key mediators in the interplay between keratinocytes and immune cells. These discoveries contribute to the development and application of biologics in
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the treatment of psoriasis patients. The thickened skin lesions in psoriasis likely represent a resource-limited microenvironment and, how different cells manage resource allocation is a critical question. Hence, different cells need to reprogram their metabolic patterns and establish beneficial metabolic crosstalk to coexist. However, our understanding of the metabolic reprogramming of keratinocytes and their metabolic crosstalk with other cell types in psoriasis is still limited.
To address these issues, in Chapters 2 and 3, we first studied the miR-31-induced metabolic reprogramming in keratinocytes, which was found to enhance glutamine metabolism and promote the secretion of immune molecules and metabolites. The composition of these secreted substances facilitate the differentiation of CD4+ naïve T cells into Th17 cells. Especially, aspartate was found to enhance Th17 cell differentiation induced by IL-6 and TGFβ, by upregulating glycolysis to sustain the malate aspartate shuttle (MAS) and increase oxidative phosphorylation of Th17 cells. Subsequent in vitro and in vivo experiments demonstrated that targeting GLS (inhibiting glutaminolysis), SLC1A3 (blocking aspartate uptake), or GOT1 (inhibiting aspartate metabolism) can reduce Th17 cell differentiation and alleviated skin inflammation in a mouse model of psoriasis. Notably, aspartate was found elevated in the serum of psoriasis patients. In addition, the psoriasis-derived CD4+ naïve T cells expressed high levels of GOT1 and MDH1 and increased the aspartate and glutamate metabolism pathway as compared to those from healthy subjects. Collectively, our in vitro and in vivo results demonstrate that highly expressed miR-31 in keratinocytes can influence the local and systemic metabolic environment and build metabolic crosstalk with immune cells to amplify the inflammatory feedback loop in psoriasis.
In Chapter 4, we demonstrate that the metabolites in the serum of psoriasis patients mediate crosstalk between different types of immune cells upon treatment with Methotrexate. These findings highlight the pervasive presence of metabolic crosstalk and its significant contribution to the therapeutic effects of methotrexate in treating psoriasis. In Chapter 5, we show that PSORI-CM02, a Chinese herbal formula that is used clinically in the treatment of psoriasis, effectively reduced HK2 expression and attenuated glycolysis in keratinocytes through the mTOR pathway.
In conclusion, we uncovered the metabolic reprogramming of psoriasis keratinocytes and their metabolic crosstalk with CD4+ naïve T cells. We also provided initial insights into the therapeutic potential of targeting either the glutamine-dependent differentiated keratinocytes or the glucose-dependent proliferating keratinocytes, as well as blocking the aspartate-dependent metabolic crosstalk between keratinocytes and CD4+ naïve T cells. These studies have expanded our understanding of the interaction mechanisms between keratinocytes and immune cells, introducing metabolites such as aspartate as novel mediators and offering new strategies for the treatment of psoriasis.
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