Post-injury immunosuppression and secondary infections are caused by an AIM2 inflammasome-driven signaling cascade

• Published in: Immunity (Cambridge, Mass.) Mass.), 2021-04, Vol.54 (4), p.648-659.e8
• Main Authors: Roth, Stefan, Cao, Jiayu, Singh, Vikramjeet, Tiedt, Steffen, Hundeshagen, Gabriel, Li, Ting, Boehme, Julia D., Chauhan, Dhruv, Zhu, Jie, Ricci, Alessio, Gorka, Oliver, Asare, Yaw, Yang, Jun, Lopez, Mary S., Rehberg, Markus, Bruder, Dunja, Zhang, Shengxiang, Groß, Olaf, Dichgans, Martin, Hornung, Veit, Liesz, Arthur
• Format: Article
• Language: English
• Subjects: AIM2; Antibodies; Apoptosis; Bacterial diseases; burn; Cell activation; Cell death; Cell survival; Cytokines; Cytotoxicity; Deoxyribonucleic acid; DNA; Experiments; Fas; FasL protein; IL-1; IL-1β; Immunology; Immunosuppression; Infections; inflammasome; Inflammasomes; Injuries; Interleukins; Ischemia; Lymphocytes; Lymphocytes T; Lymphopenia; Monocytes; Mortality; Population; Stroke; T cell; tissue injury; Tumor necrosis factor-TNF
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.02.004

Loss of lymphocytes, particularly T cell apoptosis, is a central pathological event after severe tissue injury that is associated with increased susceptibility for life-threatening infections. The precise immunological mechanisms leading to T cell death after acute injury are largely unknown. Here, we identified a monocyte-T cell interaction driving bystander cell death of T cells in ischemic stroke and burn injury. Specifically, we found that stroke induced a FasL-expressing monocyte population, which led to extrinsic T cell apoptosis. This phenomenon was driven by AIM2 inflammasome-dependent interleukin-1β (IL-1β) secretion after sensing cell-free DNA. Pharmacological inhibition of this pathway improved T cell survival and reduced post-stroke bacterial infections. As such, this study describes inflammasome-dependent monocyte activation as a previously unstudied cause of T cell death after injury and challenges the current paradigms of post-injury lymphopenia. [Display omitted] •Release of cell-free DNA after injury mediates systemic AIM2 inflammasome activation•Inflammasome-derived IL-1β secretion induces FasL expression on splenic monocytes•FasL-positive monocytes induce Fas-dependent extrinsic T cell apoptosis•Inflammasome-mediated T cell apoptosis increases risk of post-injury bacterial infections Acute tissue injuries result in systemic T cell loss that predisposes individuals to life-threatening infections. Roth et al. uncover a mechanism by which monocytes sense injury-released DNA via the AIM2 inflammasome and induce the extrinsic cell death of T cells.