2019 IARS Mentored Research Award
Benjamin Steinberg, MD, PhD, FRCPC
The Hospital for Sick Children
Assistant Professor, Staff Anesthesiologist
Toronto, Ontario, Canada
Dr. Steinberg’s Research
The role of pyroptosis in neuropathic pain
Neuropathic pain (NeuP) is a critical public health challenge, affecting 5-10% of the general population. Patients with NeuP experience increased rates of mood disorders and sleep disturbance, which contribute to reduced quality of life and societal costs through decreased productivity and employment. The enormity of this problem speaks to the difficulty in managing NeuP. While anesthesiologists and pain specialists employ a broad range of therapies to treat NeuP, virtually all are associated with significant side-effects and limited efficacy. Effective management strategies and an improved understanding of NeuP pathogenesis would better serve the millions of adults suffering from this devastating condition.
NeuP results from nerve dysfunction driven in part by proinflammatory cytokines. A subset of these important cytokines is secreted from immune cells through a pore made by the gasdermin D protein in an inflammation-driven process termed pyroptosis. To date, no published studies have demonstrated a role for pyroptosis in human or experimental NeuP.
Our overall objective is to investigate the fundamental interaction between the nervous and immune systems in the pathogenesis of NeuP. Our central hypothesis is that pyroptosis-mediated cytokine secretion drives NeuP development, and blockade of pyroptosis through gasdermin D inhibition may yield a novel therapeutic strategy for NeuP.
Using spared nerve injury and nucleus pulposus mouse NeuP models, we will evaluate nociceptive behavior. Pyroptosis will be blocked using gasdermin D genetic knockout or its inhibitor disulfiram. In vitro assays will probe the pyroptosis pathway in immune cells to identify potential loci for therapeutic intervention.
These studies will provide mechanistic insight into the inflammatory basis of NeuP and identify a new therapeutic target for drug development and investigation. Our goal is to perform fundamental and translational research in order to help our patients combat NeuP.
Glycine inhibits NINJ1 membrane clustering to suppress plasma membrane rupture in cell death
Jazlyn P Borges, Ragnhild SR Sætra, Allen Volchuk, Marit Bugge, Pascal Devant, Bjørnar Sporsheim, Bridget R Kilburn, Charles L Evavold, Jonathan C Kagan, Neil M Goldenberg, Trude Helen Flo, Benjamin Ethan Steinberg
First recognized more than 30 years ago, glycine protects cells against rupture from diverse types of injury. This robust and widely observed effect has been speculated to target a late downstream process common to multiple modes of tissue injury. The molecular target of glycine that mediates cytoprotection, however, remains elusive. The authors show that glycine works at the level of NINJ1, a newly identified executioner of plasma membrane rupture in pyroptosis, necrosis, and post-apoptosis lysis. NINJ1 is thought to cluster within the plasma membrane to cause cell rupture. The authors demonstrate that the execution of pyroptotic cell rupture is similar for human and mouse NINJ1 and that NINJ1 knockout functionally and morphologically phenocopies glycine cytoprotection in macrophages undergoing lytic cell death. Next, they show that glycine prevents NINJ1 clustering by either direct or indirect mechanisms. In pyroptosis, glycine preserves cellular integrity but does not affect upstream inflammasome activities or accompanying energetic cell death. By positioning NINJ1 clustering as a glycine target, the data resolve a long-standing mechanism for glycine-mediated cytoprotection. This new understanding will inform the development of cell preservation strategies to counter pathologic lytic cell death.
Modulation of Pathological Pain by Epidermal Growth Factor Receptor
Jazlyn P. Borges, Katrina Mekhail, Gregory D. Fairn, Costin N. Antonescu, Benjamin E. Steinberg
Chronic pain has been widely recognized as a major public health problem that impacts multiple aspects of patient quality of life. Unfortunately, chronic pain is often resistant to conventional analgesics, which are further limited by their various side effects. New therapeutic strategies and targets are needed to better serve the millions of people suffering from this devastating disease. To this end, recent clinical and preclinical studies have implicated the epidermal growth factor receptor signaling pathway (EGFR) in chronic pain states. The authors review the clinical and preclinical evidence implicating EGFR in pathological pain states and provide an overview of EGFR signaling highlighting how EGFR and its ligands drive pain hypersensitivity and interact with important pain pathways such as the opioid system.
Indirect regulation of HMGB1 release by gasdermin D
Allen Volchuk, Anna Ye, Leon Chi, Benjamin E. Steinberg, Neil M. Goldenberg
The protein high-mobility group box 1 (HMGB1) is released into the extracellular space in response to many inflammatory stimuli, where it is a potent signaling molecule. Although much research has focused on downstream HMGB1 signaling, the means by which HMGB1 exits the cell is controversial. Here the authors demonstrate that HMGB1 is not released from bone marrow-derived macrophages (BMDM) after lipopolysaccharide (LPS) treatment. They also explore whether HMGB1 is released via the pore-forming protein gasdermin D after inflammasome activation, as is the case for IL-1β. Together, data from this study demonstrate that in vitro HMGB1 release after inflammasome activation occurs after cellular rupture, which is probably inflammasome-independent in vivo.
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