Blimp-1 molds the epigenetic architecture of IL-21-mediated autoimmune diseases through an autoregulatory circuit.

Autor:	Liu YW; Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China., Fu SH; National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli, Taiwan, Republic of China.; Department and Graduate Institute of Microbiology and Immunology, and., Chien MW; National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli, Taiwan, Republic of China.; Department and Graduate Institute of Microbiology and Immunology, and., Hsu CY; Department and Graduate Institute of Microbiology and Immunology, and.; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China., Lin MH; Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China., Dong JL; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China., Lu RJ; Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan, Republic of China.; Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA., Lee YJ; Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan, Republic of China., Chen PY; Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan, Republic of China., Wang CH; Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China., Sytwu HK; Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.; National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli, Taiwan, Republic of China.; Department and Graduate Institute of Microbiology and Immunology, and.; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2022 Jun 08; Vol. 7 (11). Date of Electronic Publication: 2022 Jun 08.
DOI:	10.1172/jci.insight.151614
Abstrakt:	Positive regulatory domain 1 (PRDM1) encodes B lymphocyte-induced maturation protein 1 (BLIMP1), also known as a master regulator of T cell homeostasis. We observed a negative relationship between Blimp-1 and IL-21 based on our previous data that Blimp-1 overexpression in T cells suppresses autoimmune diabetes while Blimp-1-deficient T cells contribute to colitis in NOD mice. Reanalysis of published data sets also revealed an inverse correlation between PRDM1 and IL21 in Crohn's disease. Here, we illustrate that Blimp-1 repressed IL-21 by reducing chromatin accessibility and evicting an IL-21 activator, c-Maf, from the Il21 promoter. Moreover, Blimp-1 overexpression-mediated reduction in permissive chromatin structures at the Il21 promoter could override IL-21-accelerated autoimmune diabetogenesis in small ubiquitin-like modifier-defective c-Maf-transgenic mice. An autoregulatory feedback loop to harness IL-21 expression was unveiled by the evidence that IL-21 addition induced time-dependent Blimp-1 expression and subsequently enriched its binding to the Il21 promoter to suppress IL-21 overproduction. Furthermore, intervention of this feedback loop by IL-21 blockade, with IL-21R.Fc administration or IL-21 receptor deletion, attenuated Blimp-1 deficiency-mediated colitis and reinforced the circuit between Blimp-1 and IL-21 in the regulation of autoimmunity. We highlight the translation of Blimp-1-based epigenetic and transcriptomic profiles applicable to a personalized medicine approach in autoimmune diseases.
Databáze:	MEDLINE
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