Enforced CARD11/MALT 1 signaling in dendritic cells triggers hemophagocytic lymphohistiocytosis

• 成果类型: Article
• 署名作者: Isay, Sophie E.; Vornholz, Larsen; Schnalzger, Theresa; Groll, Tanja; Magg, Thomas; Loll, Patricia; Weirich, Gregor; Steiger, Katja; Hauck, Fabian; Ruland, Juergen
• 署名单位: Technical University of Munich; Technical University of Munich; Technical University of Munich; University of Munich; Helmholtz Association; German Cancer Research Center (DKFZ); Technical University of Munich; German Center for Infection Research
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8795
• DOI: 10.1073/pnas.2413162121
• 发表日期: 2024-12-17
• 关键词: t-cell; mutations; malt1; carma1; FAMILY; IMPACT

摘要

Hemophagocytic lymphohistiocytosis (HLH) is a life- threatening syndrome fueled by uncontrolled mononuclear phagocyte activity, yet the innate immune mechanisms driving HLH pathogenesis remain elusive. Germline gain- of- function (GOF) mutations in CARD11, a pivotal regulator of lymphocyte antigen receptor signaling, cause the is frequently associated with HLH development. Given that CARD11 is physiologically expressed not only in lymphocytes but also in dendritic cells (DCs), we explored whether enforced CARD11 signaling in DCs contributes to immunopathology. We demonstrated that exclusive DC- intrinsic expression of CARD11- GOF in mice was sufficient to induce a lethal autoinflammatory syndrome that mimicked human HLH. inflammatory cytokine production via MALT1 paracaspase engagement. Genetic deletion of Malt1 in CARD11- GOF- expressing animals reversed the hyperinflammatory phenotype. These results highlight the significant role of enforced CARD11/MALT1 signaling in DCs as a contributor to HLH pathology and suggest potential therapeutic strategies for HLH treatment.