Kevin Wilhelmsen, PhD
Innate immune receptors, including Toll-like receptors (TLRs), recognize conserved components of microorganisms, and endogenous factors released by compromised cells, to initiate an inflammatory response. The majority of research to date has focused on TLR signaling outcomes in mononuclear leukocytes, and only recently has it been appreciated that TLRs expressed in endothelial cells (ECs) can directly initiate a pivotal inflammatory response to infection or sterile injury. Since activation and dysregulated endothelial function, and interactions between ECs and leukocytes, are centrally involved in organ failure in a variety of inflammatory diseases, the identification of novel TLR EC specific signaling components, and cellular mechanisms that regulate endothelial activation, may lead to new understandings and therapeutics for inflammatory disorders. There are two major focuses of my research:
The first focus investigates the biological outcomes and signaling pathways that are initiated after the Toll-like receptor (TLR)-dependent activation of ECs. We recently made the novel discovery that the MAP kinase ERK5 is a central, pro-inflammatory mediator of TLR, TNFa and IL-1ß signaling pathways in ECs, and its inhibition reduces systemic inflammation and mortality in mouse endotoxemia models. Currently, we are more thoroughly delving into the role of ERK5 in both infectious and non-infectious disease models, and better refining its relationship to other innate immune signaling pathways.
The second focus examines how the endocannabinoid (eCB) system modulates inflammation in ECs. We recently made the novel discovery that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA) reduce EC inflammatory responses induced by bacterial TLR agonists and TNFa. Furthermore, we found that primary human ECs from multiple organs express all of the known eCB metabolic enzymes, and the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel TRPV1. However, in contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Our results suggest that human ECs have the machinery to metabolize and respond to cannabinoids, and that the endothelial eCB system represents a novel target for inflammatory disorder therapies. Currently, we are in the process of expanding these studies to include other eCBs, and classes of cannabinoids, and determining the mechanism by which WIN55,212-2 and NADA modulate EC activation.
Immunology, Innate Immunity, Inflammation, Sepsis, Toll-like Receptors, Cannabinoids, Endocannabinoids, Cannabinoid Receptors, TRP Channels, Cell Biology, Biochemistry, Intracellular Signaling, Tyrosine Kinases
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