The Role Of Dermal Fibroblasts In The Pathogenesis Of Lithium-induced Psoriasis

Psoriasis is a debilitating inflammatory chronic condition of the skin caused by aberrant activation of Th1/Th17 cells.It is characterized by well-demarcated,raised areas of erythematous plaques,often covered by silvery scaling,and can involve multiple systems.There is currently no cure for this disease.In addition to genetic factors,the incidence of psoriasis is also related to environmental factors.Certain environment factors such as infection,injury,stress and drugs can induce and exacerbates psoriasis.Imiquimod(IMQ)is a drug for the treatment of condyloma acuminatum,and lithium is the first-line drug for the treatment of bipolar disorder.Their side effects are to induce psoriasis,but the underlying mechanism is still unclear.Psoriasis and obesity are comorbidities,but the pathological relationship is unclear.Dermal fibroblasts are cells within the dermis layer of skin which are responsible for generating connective tissue and allowing the skin to recover from injury.Dermal fibroblasts can proliferate and commit into preadipocytes,and then differentiate into mature adipocytes.At present,the research on the pathogenesis of psoriasis mainly focuses on immune cells and keratinocytes,but the important role of dermal fibroblasts in the pathogenesis of psoriasis has not been realized.And the mechanism of the comorbidities of psoriasis and obesity is not yet clear.Therefore,by constructing IMQinduced psoriasis models and in vitro and in vivo experiments of lithium,combined with RNA sequencing analysis,we reveals the mechanism of dermal fibroblasts in the pathogenesis of psoriasis.We found that the key link between psoriasis and obesity is the apparent accumulation of fat pre-cells.Lithium can activate the wnt pathway to inhibit inflammation and promote the proliferation of fibroblasts and its commitment into preadipocyte,and inhibit their differentiation into adipocytes.Long-term lithium feed feeding can exacerbate psoriasis,while short-term lithium feed feeding inhibits IMQ-induced psoriasis.The difference between short-term and long-term lithium feed is whether there are accumulated preadipocytes.Accumulated preadipocytes can highly express wnt inhibitors to inhibit the inhibitory effect of wnt pathway on the expression of immune factors in infiltrating immune cells,thereby exacerbating the occurrence of psoriasis.Collectively,our findings reveal that preadipocytes are potential targets for the occurrence of psoriasis and that preadipocytes are mediators that coordinate the wnt pathway and inflammatory pathways,suggesting that preadipocytes may serve as novel targets for the treatment of skin diseases.