Trauma-associated extracellular histones mediate inflammation via a MYD88-IRAK1-ERK signaling axis and induce lytic cell death in human adipocytes.
Julian RoosJulia ZinngrebeMarkus S Huber-LangLudmila LupuMiriam A SchmidtHannah StrobelMike-Andrew WesthoffUlrich StifelFlorian GebhardMartin WabitschTom Eirik MollnesKlaus-Michael DebatinRebecca HalbgebauerPamela Fischer-PosovszkyPublished in: Cell death & disease (2024)
Despite advances in the treatment and care of severe physical injuries, trauma remains one of the main reasons for disability-adjusted life years worldwide. Trauma patients often suffer from disturbances in energy utilization and metabolic dysfunction, including hyperglycemia and increased insulin resistance. White adipose tissue plays an essential role in the regulation of energy homeostasis and is frequently implicated in traumatic injury due to its ubiquitous body distribution but remains poorly studied. Initial triggers of the trauma response are mainly damage-associated molecular patterns (DAMPs) such as histones. We hypothesized that DAMP-induced adipose tissue inflammation contributes to metabolic dysfunction in trauma patients. Therefore, we investigated whether histone release during traumatic injury affects adipose tissue. Making use of a murine polytrauma model with hemorrhagic shock, we found increased serum levels of histones accompanied by an inflammatory response in white adipose tissue. In vitro, extracellular histones induced an inflammatory response in human adipocytes. On the molecular level, this inflammatory response was mediated via a MYD88-IRAK1-ERK signaling axis as demonstrated by pharmacological and genetic inhibition. Histones also induced lytic cell death executed independently of caspases and RIPK1 activity. Importantly, we detected increased histone levels in the bloodstream of patients after polytrauma. Such patients might benefit from a therapy consisting of activated protein C and the FDA-approved ERK inhibitor trametinib, as this combination effectively prevented histone-mediated effects on both, inflammatory gene activation and cell death in adipocytes. Preventing adipose tissue inflammation and adipocyte death in patients with polytrauma could help minimize posttraumatic metabolic dysfunction.
Keyphrases
- adipose tissue
- trauma patients
- insulin resistance
- inflammatory response
- oxidative stress
- cell death
- diabetic rats
- high fat diet
- end stage renal disease
- endothelial cells
- high glucose
- ejection fraction
- toll like receptor
- signaling pathway
- lipopolysaccharide induced
- dna methylation
- chronic kidney disease
- newly diagnosed
- cell proliferation
- spinal cord injury
- healthcare
- lps induced
- polycystic ovary syndrome
- high fat diet induced
- prognostic factors
- high resolution
- quality improvement
- palliative care
- pi k akt
- mental health
- skeletal muscle
- cell therapy
- klebsiella pneumoniae
- small molecule
- multiple sclerosis
- mass spectrometry
- physical activity
- early onset
- type diabetes
- single molecule
- stem cells
- high speed
- amino acid
- chronic pain