Altered Inflammasome and Immune activation in Paediatric Traumatic Brain Injury

Abstract

Abstract Introduction: Systemic Inflammation is associated with Traumatic Brain Injury (TBI) and therefore is a potential target for immunomodulation. Dysregulated immune function post-TBI increased susceptibility to infection and post-concussive syndrome. The inflammasome is a protein complex associated with an amplified proinflammatory response and is a potential target for immunomodulation that preserves antimicrobial immunity. Methods: Samples from children with mild TBI (mTBI; Glasgow coma scale (GCS) 14/15), severe TBI (sTBI; GCS < 8) and control children were collected at baseline and two week follow up and were treated with endotoxin and melatonin. Toll-like receptor (TLR4; marker of endotoxin responses) and CD11b (activation marker) expression on neutrophils and monocytes were evaluated by flow cytometry. Inflammasome-related genes and cytokines were assessed using TaqMan RT-PCR samples ELISA sandwich immunoassay, respectively. Results: A total of 214 children were enrolled including: TBI (n = 116), with mild TBI (mTBI; Glasgow coma scale (GCS) 14/15) and severe TBI (sTBI; GCS < 8), and (n = 98) control patients collected at baseline and two week follow up. Total monocyte and intermediate monocyte populations were reduced in mTBI at baseline. Neutrophil CD11b and TLR4 expression was decreased in mTBI at 10–14 days. NLRP3 and NLRP1 were downregulated at 10–14 days while IL-1β was increased at baseline at 0–4 days and further elevated by 10–14 days and significantly higher in those with no previous mTBI. Serum cytokines showed lower IL-18 and raised IL-33 in those with mTBI. Prior concussion did not influence serum cytokine levels. In addition, LPS did not stimulate an IL-18 and IL-1β response in the mTBI group at 10–14 days. Conclusions: Children with mTBI had reduced CD11b and TLR4 expression and NLRP3 inflammasome activation. IL-1β mRNA was raised and continued to rise after injury implicating the innate immune system in the subacute phase of injury. Immune dysregulation post-TBI in children may be a target for immunomodulation following further exploration in vitro of potential mechanisms and therapies.