TREML4 receptor regulates inflammation and innate immune cell death during polymicrobial sepsis

Christina Nedeva1, Joseph Menassa1, Mubing Duan1, Chuanxin Liu1, Marcel Doerflinger2,3, Andrew J Kueh3,4, Marco J Herold3,4, Pamali Fonseka1, Thanh Kha Phan1, Pierre Faou1, Harinda Rajapaksha1, Weisan Chen1, Mark D Hulett1, Hamsa Puthalakath5

  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
  2. Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
  3. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  4. Blood Cell and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
  5. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia. h.puthalakath@latrobe.edu.au.

Abstract

Sepsis is a biphasic disease characterized by an acute inflammatory response, followed by a prolonged immunosuppressive phase. Therapies aimed at controlling inflammation help to reduce the time patients with sepsis spend in intensive care units, but they do not lead to a reduction in overall mortality. Recently, the focus has been on addressing the immunosuppressive phase, often caused by apoptosis of immune cells. However, molecular triggers of these events are not yet known. Using whole-genome CRISPR screening in mice, we identified a triggering receptor expressed on myeloid cells (TREM) family receptor, TREML4, as a key regulator of inflammation and immune cell death in sepsis. Genetic ablation of Treml4 in mice demonstrated that TREML4 regulates calcium homeostasis, the inflammatory cytokine response, myeloperoxidase activation, the endoplasmic reticulum stress response and apoptotic cell death in innate immune cells, leading to an overall increase in survival rate, both during the acute and chronic phases of polymicrobial sepsis.

Presented By Christina Nedeva | ORCID iD

Immunology & MicrobiologyNicholas Liao2020-10 (Oct)