Tacrolimus prevents complement‐mediated Nod‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis of mesenchymal stem cells from immune thrombocytopenia

• Published in: British journal of haematology Vol. 202; no. 5; pp. 995 - 1010
• Main Authors: Cai, Xuan, Wu, Jin, An, Zhuo‐Yu, Wang, Chen‐Cong, Zhu, Xiao‐Lu, He, Yun, Fu, Hai‐Xia, Huang, Xiao‐Jun, Zhang, Xiao‐Hui
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.09.2023
• Subjects: Adipocytes; Adiponectin; Autoimmune diseases; Caspase; complement; Fatty acids; Hematology; Idiopathic thrombocytopenic purpura; Immunomodulation; Inflammasomes; Megakaryocytes; Mesenchymal stem cells; NLRP3 inflammasome; Oxidation; Pyrin protein; Pyroptosis; Reactive oxygen species; Stem cells; Tacrolimus; Thrombocytopenia; Transcriptomes; adiponectin; NLRP3 inflammasome; complement; mesenchymal stem cells; tacrolimus
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.18625

Summary The abnormal immunomodulatory functions of mesenchymal stem cells (MSCs) have been implicated in the development of immune thrombocytopenia (ITP). Recent studies have suggested important effects of complement on immune cell function. However, whether complement modulates bone marrow MSCs function in ITP is poorly defined. Tacrolimus has recently been applied to the treatment of autoimmune diseases. Here, we explored whether impaired ITP‐MSCs could be targeted by tacrolimus. Our results showed that the Nod‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome was activated in ITP MSCs with complement deposition (MSCs‐C+) and initiated caspase‐1‐dependent pyroptosis. Transcriptome sequencing results showed abnormal fatty acid metabolism in MSCs‐C+. Enhanced fatty acid β‐oxidation and reactive oxygen species production activated the NLRP3 inflammasome. Adipocytes derived from MSCs‐C+ secreted less adiponectin. Adiponectin promoted the differentiation of megakaryocytes and inhibited the destruction of platelets. Tacrolimus inhibited NLRP3 inflammasome activation and MSCs‐C+ pyroptosis in vitro and in vivo. Tacrolimus plus danazol elicited a higher sustained response than danazol monotherapy in corticosteroid‐resistant patients with ITP. Our findings demonstrate that the activation of the NLRP3 inflammasome in ITP MSCs mediated by complement could be inhibited by tacrolimus, which might be a potential new therapy for ITP.