Indiana University-Purdue University Indianapolis (IUPUI) / Damage Associated Molecular Patterns (DAMPs) act largely as endogenous ligands to initiate and maintain the signaling of both inflammatory processes and the acquired immune response. Prolonged action of these endogenous signals are thought to play a significant role sterile inflammation which may be integral to the development of chronic inflammation pathology.
HMGB1 (High Mobility Group Box 1) is a highly conserved non-acetylated protein which is among the most important chromatin proteins and serves to organize DNA and regulate transcription. Following stress or injury to the cell, hyperacetylation of lysine residues causes translocation of HMGB1 and eventual release into the extracellular environment where it can take the form of a DAMP and interact with cell types bearing either the Receptor for Advanced Glycation End-products (RAGE) or Toll-Like Receptor 4 (TLR4). Activation of these surface receptors contribute directly to both acute and chronic inflammation.
This project investigated the role of HMGB1 through its receptors Receptor for Advanced Glycation End-products (RAGE) and Toll-Like Receptor 4 (TLR4) as it pertained to the development of chronic inflammation and pathology in small diameter, nociceptive sensory neurons. It was demonstrated that the neuronal signaling associated with exposure to HMGB1 is dependent upon the ligands conformational states, as the state dictates its affinity and types of neuronal response.
Neuronal activation by bacterial endotoxin or the disulfide state of HMGB1 is dependent on TLR4 and the associated signaling adapter protein, Myeloid differentiation primary response gene 88 (MYD88). Interruption of the receptor-mediated signaling cascade associated with MyD88 was shown to be sufficient to mitigate ligand-dependent neuronal activation and demonstrated significant behavioral findings. Further downstream signaling of HMGB1 in the neuron has yet to be identified, however important steps have been taken to elucidate the role of chronic neuroinflammation with hopes of eventual translational adaptation for clinical therapeutic modalities.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/7339 |
| Date | 02 April 2015 |
| Creators | Allette, Yohance Mandela |
| Contributors | White, Fletcher A., Bidwell, Joseph P., Harrington, Maureen A., Jones, Kathryn J. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
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