Psoriasis is characterized by abnormal proliferation of keratinocytes,as well as infiltration of immune cells into the dermis and epidermis,causing itchy,scaly and erythematous plaques of skin.The understanding of thi...Psoriasis is characterized by abnormal proliferation of keratinocytes,as well as infiltration of immune cells into the dermis and epidermis,causing itchy,scaly and erythematous plaques of skin.The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently.Here,we showed that IMMH002,a novel orally active S1 P1 modulator,desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus.Using different psoriasis animal models,we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PAS I score and pathological injure evaluation.Mechanistically,IMMH002 regulated CD3+T lymphocytes re-distribution by inducing lymphocytes’homing,thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus.Our results suggest that the novel SIP1 agonist,IMMH002,exert extraordinary capacity to rapidly modulate T lymphocytes distribution,representing a promising drug candidate for psoriasis treatment.展开更多
Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease with unclear etiology and limited treatment options.The median survival time for IPF patients is approximately 2–3 years and there is no effective inter...Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease with unclear etiology and limited treatment options.The median survival time for IPF patients is approximately 2–3 years and there is no effective intervention to treat IPF other than lung transplantation.As important components of lung tissue,endothelial cells(ECs)are associated with pulmonary diseases.However,the role of endothelial dysfunction in pulmonary fibrosis(PF)is incompletely understood.Sphingosine-1-phosphate receptor 1(S1PR1)is a G protein-coupled receptor highly expressed in lung ECs.Its expression is markedly reduced in patients with IPF.Herein,we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin(BLM)challenge.Selective activation of S1PR1 with an S1PR1 agonist,IMMH002,exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier.These results suggest that S1PR1 might be a promising drug target for IPF therapy.展开更多
基金supported by the CAMS Innovation Fund for Medical Sciences(2016-I2M-3-008,China)National Natural Science Foundation of China(NSFC Nos.81872923 and 81473096)+1 种基金Beijing Natural Science Foundation(No.7172140,China)The Drug Innovation Major Project(No.2018ZX09711001-003,China).
文摘Psoriasis is characterized by abnormal proliferation of keratinocytes,as well as infiltration of immune cells into the dermis and epidermis,causing itchy,scaly and erythematous plaques of skin.The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently.Here,we showed that IMMH002,a novel orally active S1 P1 modulator,desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus.Using different psoriasis animal models,we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PAS I score and pathological injure evaluation.Mechanistically,IMMH002 regulated CD3+T lymphocytes re-distribution by inducing lymphocytes’homing,thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus.Our results suggest that the novel SIP1 agonist,IMMH002,exert extraordinary capacity to rapidly modulate T lymphocytes distribution,representing a promising drug candidate for psoriasis treatment.
基金supported by National Key Research&Development Program from the Ministry of Science and Technology of the PRC(No.2019YFE0111800,China)National Natural Science Foundation of China(No.81872923,China)+1 种基金Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2021-JKCS-016,China)The Science and Technology Development Fund,Macao SAR(No.0074/2019/AMJ,China).
文摘Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease with unclear etiology and limited treatment options.The median survival time for IPF patients is approximately 2–3 years and there is no effective intervention to treat IPF other than lung transplantation.As important components of lung tissue,endothelial cells(ECs)are associated with pulmonary diseases.However,the role of endothelial dysfunction in pulmonary fibrosis(PF)is incompletely understood.Sphingosine-1-phosphate receptor 1(S1PR1)is a G protein-coupled receptor highly expressed in lung ECs.Its expression is markedly reduced in patients with IPF.Herein,we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin(BLM)challenge.Selective activation of S1PR1 with an S1PR1 agonist,IMMH002,exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier.These results suggest that S1PR1 might be a promising drug target for IPF therapy.
