TY - JOUR
T1 - CRISPRa engineered Elite macrophages enable adoptive cell therapy for rheumatoid arthritis
AU - Huang, Yuhong
AU - Wang, Zhuqian
AU - Zhong, Chuanxin
AU - Chen, Hongzhen
AU - Chen, Xinxin
AU - Cao, Chunhao
AU - Qiu, Fang
AU - Xie, Duoli
AU - Li, Jin
AU - Li, Jie
AU - Yang, Xu
AU - Lu, Aiping
AU - Fu, Xuekun
AU - Liang, Chao
N1 - The authors acknowledge the assistance of Southern University of Science and Technology Core Research Facilities, the Microscope and Imaging Center and the Experimental Animal Center of Southern University of Science and Technology. Fig. S4A was created with BioRender.com. This work is supported by the National Natural Science Foundation Council of China (82172386 and 81922081 to C.L., and 82100943 to X.F.), the Department of Education of Guangdong Province (2021KTSCX104 to C.L.), the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab) (2020B1212030006 to A.L.), the Guangdong Basic and Applied Basic Research Foundation (2022A1515012164 to C.L., and 2023A1515012000 to X.F.), the Science, Technology and Innovation Commission of Shenzhen (JCYJ20210324104201005 to C.L., and JCYJ20220530115006014 to X.F.), the Shenzhen Medical Research Fund (A2303061 to X.F.), the Hong Kong General Research Fund (12102722 to A.L.), and the Hong Kong RGC Theme-based Research Scheme (T12-201/20-R to A.L.).
PY - 2024/3/20
Y1 - 2024/3/20
N2 - Rheumatoid arthritis (RA) is a poly-articular systemic autoimmune disorder characterized by infiltration of immune cells, synovial hyperplasia and joint destruction. Macrophages (MΦs) can polarize into either pro-inflammatory M1 or anti-inflammatory M2 phenotype in response to different environmental signals. In RA, MΦs are prone to polarize into the M1 phenotype. Reprogramming MΦs has shown promise in treating diseases, e.g., the chimeric antigen receptor-MΦ (CAR-M)-based adoptive immunotherapy. Interleukin-10 (IL-10) is one of the pivotal factors for M2 polarization. Clustered regularly interspaced short palindromic repeats-based transcriptional activation (CRISPRa) harnesses the native machinery in cells to enable a quick and efficient increase of endogenous gene expression. Here, we combined a CRISPRa system with adoptive cell therapy to construct engineered lastingly interleukin-ten (IL-10) expressed MΦs (Elite MΦs). The Elite MΦs possessed powerful anti-inflammatory capability and represented a pre-activated state of M2 MΦs in vitro. The Elite MΦs were more susceptible to an M2 inducer while resistant to M1 inducers. The Elite MΦs displayed enhanced chemotactic characteristics, leading to accumulated in vivo distribution at inflamed sites. Systemic administration of the Elite MΦs relieved inflammation, synovial hyperplasia and joint destruction in mouse models of RA. The Elite MΦs constructed by CRISPRa hold promise for addressing the current unmet medical need in RA.
AB - Rheumatoid arthritis (RA) is a poly-articular systemic autoimmune disorder characterized by infiltration of immune cells, synovial hyperplasia and joint destruction. Macrophages (MΦs) can polarize into either pro-inflammatory M1 or anti-inflammatory M2 phenotype in response to different environmental signals. In RA, MΦs are prone to polarize into the M1 phenotype. Reprogramming MΦs has shown promise in treating diseases, e.g., the chimeric antigen receptor-MΦ (CAR-M)-based adoptive immunotherapy. Interleukin-10 (IL-10) is one of the pivotal factors for M2 polarization. Clustered regularly interspaced short palindromic repeats-based transcriptional activation (CRISPRa) harnesses the native machinery in cells to enable a quick and efficient increase of endogenous gene expression. Here, we combined a CRISPRa system with adoptive cell therapy to construct engineered lastingly interleukin-ten (IL-10) expressed MΦs (Elite MΦs). The Elite MΦs possessed powerful anti-inflammatory capability and represented a pre-activated state of M2 MΦs in vitro. The Elite MΦs were more susceptible to an M2 inducer while resistant to M1 inducers. The Elite MΦs displayed enhanced chemotactic characteristics, leading to accumulated in vivo distribution at inflamed sites. Systemic administration of the Elite MΦs relieved inflammation, synovial hyperplasia and joint destruction in mouse models of RA. The Elite MΦs constructed by CRISPRa hold promise for addressing the current unmet medical need in RA.
U2 - 10.59717/j.xinn-med.2024.100050
DO - 10.59717/j.xinn-med.2024.100050
M3 - Journal article
SN - 2959-8745
VL - 2
JO - The Innovation Medicine
JF - The Innovation Medicine
IS - 1
M1 - 100050
ER -
