|Title:||NLRP3/ Caspase-1 mediated inflammation plays a critical role in repetitive brain injury associated chronic pain|
Nguyen, Tyler, Department of Anesthesia, Indiana University, Bloomington, Stark Neuroscience Research Institute, Indiana University School of Medicine; Natalie Nguyen, Stark Neuroscience Research Institute, Indiana University School of Medicine; Ashlyn Cochran, Stark Neuroscience Research Institute, Indiana University School of Medicine; Mohammed Al-Juboori, Stark Neuroscience Research Institute, Indiana University School of Medicine; Saahil Saxena, Department of Anesthesia, Indiana University, Bloomington; Jared Smith, Stark Neuroscience Research Institute, Indiana University School of Medicine; Sarah Talley, IUPUI School of Science, IUPUI; Edward Campbell, IUPUI School of Science, IUPUI; Fletcher White, 1Department of Anesthesia, Indiana University, Stark Neuroscience Research Institute, Indiana University School of Medicine Bloomington,
Background/Significance/Rationale: Patients who suffer from concussive mild traumatic brain injuries (mTBIs) often report high incidents of acute and chronic pain. Despite extensive studies investigate the underlining mechanism of mTBIs-associated pain, the role of acute and chronic inflammation after brain injury and its contribution towards long-term pain are still poorly understood. Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes and its effects on TBI-related pain.
Methods: In this study, utilizing a recently developed inflammasome reporter mouse model, we used in vivo and ex vivo bioluminescence imaging to determine the development and progression of NLRP3/caspase-1 mediated inflammatory response at multiple body areas over time.
Results/Findings: Using a murine repetitive closed head mTBIs model, we found significant increase in inflammatory signals of brain, thorax, abdomen, and paws in vivo after each injury and lasted for at least one week after the last injury. We also found enhanced in inflammation of ex vivo brain slice preparations after injury that lasted for at least 3 days after last mTBI. We also observed persistent increase in pain sensitivity with behavioral testing and lasting for more than two months after injuries. We then directly block NLRP3 inflammasome-caspase 1 activity, with MCC950, a potent NLRP3-specific inhibitor that can cross the blood brain barrier. We observed a remarkably reduction in inflammatory signals, and pain sensitivity behaviors were greatly attenuated. Immunoblotting revealed high caspase 1 protein level after in injured group but was diminished in MCC950 treatment group.
Conclusions/Discussion: These results suggest that inflammasome (NLRP3-Caspase 1) mediated inflammatory response has great contribution to the chronic nociplastic pain state after multiple head traumas and blocking NLRP3-Caspase 1 activity produced positive effects in reducing inflammation and relieving pain.
Translational/Human Health Impacts: Overall, this study provides a significant step in advancing our understanding of the short-term and long-term trauma-associated inflammatory events, which may contribute to mTBI-associated pTP. Most importantly, for the first time, it provides an effective target for therapeutic approach of chronic pain.