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

Immunity. 2021 Apr 13;54(4):648-659.e8. doi: 10.1016/j.immuni.2021.02.004. Epub 2021 Mar 4.

Abstract

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.

Keywords: AIM2; Fas; IL-1; T cell; burn; cell death; inflammasome; stroke; tissue injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • Bacterial Infections / immunology
  • Burns / immunology
  • Burns / microbiology
  • Coinfection / immunology*
  • Coinfection / microbiology
  • DNA-Binding Proteins / immunology*
  • Humans
  • Immune Tolerance / immunology*
  • Inflammasomes / immunology*
  • Interleukin-1beta / immunology
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / immunology
  • Signal Transduction / immunology*
  • Stroke / immunology
  • Stroke / microbiology
  • T-Lymphocytes / immunology

Substances

  • AIM2 protein, human
  • DNA-Binding Proteins
  • Inflammasomes
  • Interleukin-1beta