An IL-23-STAT4 pathway is required for the proinflammatory function of classical dendritic cells during CNS inflammation

• 成果类型: Article
• 署名作者: Alakhras, Nada S.; Zhang, Wenwu; Barros, Nicolas; Sharma, Anchal; Ropa, James; Priya, Raj; Yang, X. Frank; Kaplan, Mark H.
• 署名单位: Indiana University System; Indiana University Bloomington; Indiana University System; Indiana University Bloomington; Indiana University System; Indiana University Bloomington; Eli Lilly
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10899
• DOI: 10.1073/pnas.2400153121
• 发表日期: 2024-08-01
• 关键词: experimental autoimmune encephalomyelitis; central-nervous-system; ifn-gamma; multiple-sclerosis; t-cells; stat4; induction; il-23; mice; maturation

摘要

Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL- 12 and IL- 23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. To define whether STAT4 is required for intrinsic signaling in mature DC function, we used conditional mutant mice in the EAE model. Deficiency of STAT4 in CD11c- expressing cells resulted in decreased T cell priming and inflammation in the central nervous system. EAE susceptibility was recovered following adoptive transfer of wild- type bone marrow-derived DCs to mice with STAT4- deficient DCs, but not adoptive transfer of STAT4- or IL- 23R- deficient DCs. Single- cell RNA- sequencing (RNA-seq) identified STAT4- dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define an IL-23-STAT4 pathway in DCs that is key to DC function during inflammatory disease.