Grant: Project Grant

Millions of individuals worldwide suffer from brain, spinal cord and peripheral nerve injuries, which not only cause damage to neural tissue but frequently culminate in enduring chronic pain. The inflammatory response to these injuries is characterized by the activation, proliferation, and entry of immune cells into the nervous system, essential for the clearance of cellular debris. We and others have shown that the inflammatory response itself plays a critical role in inflicting secondary damage in the nervous system, causing further death of nearby neurons and myelin-producing cells. Consequently, inflammation can persist for months, or even years. Because the human nervous system is unable to repair itself, damages sustained after injury often lead to permanent motor and sensory (e.g. pain) deficits, for which no cure is available. Key contributors to neuroinflammation include the release of cellular molecules, known as danger signals or alarmins, and include the inflammatory protein interleukin (IL)-1 alpha. IL-1 alpha is normally found in tissue-resident macrophages, where it participates in gene expression regulation. However, when released after cell damage and death, it significantly activates inflammation, resulting in the production of its sister cytokine, IL-1 beta, by recruited blood immune cells. We recently found that IL-1 cytokines, beyond their inflammatory function, can directly influence pain-perceiving sensory neurons known as nociceptors, inciting pain in chronic inflammatory autoimmune diseases by binding to IL-1 receptor type 1 (IL-1R1). However, much remains to be discovered regarding the ways in which IL-1 cytokines and IL-1R1 mediate neuropathic pain. The main goal of this research proposal is to identify the cellular and molecular mechanisms involved in these responses and to utilize this knowledge to reduce pain after neural injury.