My laboratory studies the mechanisms that switch-on and switch-off inflammation and pain. Inflammation protects against infection, and the sensation of pain allows organisms to avoid stimuli that would otherwise cause injury. However, inflammation must be tightly controlled since dysregulated, exaggerated inflammation causes disease and pain. The mechanisms that initiate and terminate inflammation and pain are poorly understood, and consequently the therapies are inadequate and often associated with detrimental side effects. Our work focuses on the role of proteolytic enzymes as “molecular switches” that initiate and terminate signaling by mediators of inflammation and pain. Proteases that act at the cell-surface and in endosomes, lysosomes and proteasomes cleave neuropeptides, G-protein coupled receptors and ion channels and thereby control signaling by major mediators of inflammation and pain transmission.

Serine proteases from the circulation, inflammatory cells, epithelial tissues and the nervous system, which are generated and released during injury and inflammation, signal to sensory nerves by cleaving protease-activated receptors. Receptor activation stimulates the release of neuropeptides, which cause neurogenic inflammation of peripheral tissues and mediate nociceptive transmission in the spinal cord. Activation also causes hyperexcitability of neurons, in part by sensitizing ion channels, including members of the large family of transient receptor potential channels.

Metalloendopeptidases, which are anchored to membranes at the cell-surface and in endosomes, process neuropeptides that mediate inflammation and pain transmission, and can thereby initiate and terminate inflammatory and nociceptive signaling. Enzymes such as neprilysin degrade neuropeptides at the cell-surface, and together with proteins that mediate receptor desensitization, such as arrestins, terminate neuropeptide signaling. Other peptidases that are present in endosomes, exemplified by endothelin-converting enzyme-1, cleave endocytosed neuropeptides, thereby allowing recycling of receptors and resensitization of inflammation and pain transmission.

Proteases in lysosomes and proteasomes degrade receptors and ion channels to irrevocably terminate their ability to signal. Ubiquitin ligases covalently modify receptors and channels and thereby direct proteins to lysosomes and proteasomes, where proteolysis terminates signaling. Deubiquitinating proteases in endosomes reverse this process, allowing receptors and channels to escape degradation and continue to signal.

We seek to discover the mechanisms that switch inflammation and pain on and off through studies at the molecular, cellular and organismal level. An understanding of the mechanisms that initiate and terminate inflammation and pain will provide insights into new therapies for prevalent and debilitating human diseases. The major general question of our work is: “What are the mechanisms that initiate and terminate neurogenic inflammation and pain transmission?” Specific questions include: How do proteases signal to sensory neurons, sensitize transient receptor potential channels, and initiate neurogenic inflammation and hyperalgesia to thermal and mechanical stimuli? How do cell-surface and endosomal peptidases regulate the activity and trafficking of neuropeptide receptors? What are the mechanisms that target protease-activated receptors, neuropeptide receptors, and transient receptor potential ion channels to and from the plasma membrane?