Kevin Wilhelmsen, PhD

Assistant Adjunct Professor

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.

Khakpour S, Wilhelmsen K, Hellman J. Vascular endothelial cell Toll-like receptor pathways in sepsis. Innate Immun. 2015 Nov; 21(8):827-46.
Wilhelmsen K, Xu F, Farrar K, Tran A, Khakpour S, Sundar S, Prakash A, Wang J, Gray NS, Hellman J. Extracellular signal-regulated kinase 5 promotes acute cellular and systemic inflammation. Sci Signal. 2015 Aug 25; 8(391):ra86.
Kozicky LK, Zhao ZY, Menzies SC, Fidanza M, Reid GS, Wilhelmsen K, Hellman J, Hotte N, Madsen KL, Sly LM. Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state. J Leukoc Biol. 2015 Dec; 98(6):983-94.
Wilhelmsen K, Khakpour S, Tran A, Sheehan K, Schumacher M, Xu F, Hellman J. The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells. J Biol Chem. 2014 May 9; 289(19):13079-100.
Zhang F, Feng X, Zeng Q, Wang B, Wilhelmsen K, Li Q, Cao X, Yu B. Sevoflurane induced amnesia inhibits hippocampal Arc expression partially through 5-hydroxytryptamine-7 receptors in the bilateral basolateral amygdala in rats. Neurosci Lett. 2014 Mar 6; 562:13-8.
Wilhelmsen K, Farrar K, Hellman J. Quantitative in vitro assay to measure neutrophil adhesion to activated primary human microvascular endothelial cells under static conditions. J Vis Exp. 2013; (78):e50677.
Prakash A, Mesa KR, Wilhelmsen K, Xu F, Dodd-o JM, Hellman J. Alveolar macrophages and Toll-like receptor 4 mediate ventilated lung ischemia reperfusion injury in mice. Anesthesiology. 2012 Oct; 117(4):822-35.
Wilhelmsen K, Mesa KR, Lucero J, Xu F, Hellman J. ERK5 protein promotes, whereas MEK1 protein differentially regulates, the Toll-like receptor 2 protein-dependent activation of human endothelial cells and monocytes. J Biol Chem. 2012 Aug 3; 287(32):26478-94.
Peng Z, Zhu Y, Zhang Y, Wilhelmsen K, Jia C, Jin J, Xue Q, Feng X, Zhang F, Yu B. Effects of ghrelin on pulmonary NOD2 mRNA expression and NF-?B activation when protects against acute lung injury in rats challenged with cecal ligation and puncture. Int Immunopharmacol. 2012 Aug; 13(4):440-5.
Frijns E, Kuikman I, Litjens S, Raspe M, Jalink K, Ports M, Wilhelmsen K, Sonnenberg A. Phosphorylation of threonine 1736 in the C-terminal tail of integrin ß4 contributes to hemidesmosome disassembly. Mol Biol Cell. 2012 Apr; 23(8):1475-85.
Wilhelmsen K, Mesa KR, Prakash A, Xu F, Hellman J. Activation of endothelial TLR2 by bacterial lipoprotein upregulates proteins specific for the neutrophil response. Innate Immun. 2012 Aug; 18(4):602-16.
Shin HS, Xu F, Bagchi A, Herrup E, Prakash A, Valentine C, Kulkarni H, Wilhelmsen K, Warren S, Hellman J. Bacterial lipoprotein TLR2 agonists broadly modulate endothelial function and coagulation pathways in vitro and in vivo. J Immunol. 2011 Jan 15; 186(2):1119-30.
Frijns E, Sachs N, Kreft M, Wilhelmsen K, Sonnenberg A. EGF-induced MAPK signaling inhibits hemidesmosome formation through phosphorylation of the integrin {beta}4. J Biol Chem. 2010 Nov 26; 285(48):37650-62.
Margadant C, Frijns E, Wilhelmsen K, Sonnenberg A. Regulation of hemidesmosome disassembly by growth factor receptors. Curr Opin Cell Biol. 2008 Oct; 20(5):589-96.
Eichhorn PJ, Creyghton MP, Wilhelmsen K, van Dam H, Bernards R. A RNA interference screen identifies the protein phosphatase 2A subunit PR55gamma as a stress-sensitive inhibitor of c-SRC. PLoS Genet. 2007 Dec; 3(12):e218.
Ketema M, Wilhelmsen K, Kuikman I, Janssen H, Hodzic D, Sonnenberg A. Requirements for the localization of nesprin-3 at the nuclear envelope and its interaction with plectin. J Cell Sci. 2007 Oct 1; 120(Pt 19):3384-94.
van den Bout I, van Rheenen J, van Angelen AA, de Rooij J, Wilhelmsen K, Jalink K, Divecha N, Sonnenberg A. Investigation into the mechanism regulating MRP localization. Exp Cell Res. 2008 Jan 15; 314(2):330-41.
Wilhelmsen K, Litjens SH, Kuikman I, Margadant C, van Rheenen J, Sonnenberg A. Serine phosphorylation of the integrin beta4 subunit is necessary for epidermal growth factor receptor induced hemidesmosome disruption. Mol Biol Cell. 2007 Sep; 18(9):3512-22.
Wilhelmsen K, Ketema M, Truong H, Sonnenberg A. KASH-domain proteins in nuclear migration, anchorage and other processes. J Cell Sci. 2006 Dec 15; 119(Pt 24):5021-9.
Wilhelmsen K, Litjens SH, Sonnenberg A. Multiple functions of the integrin alpha6beta4 in epidermal homeostasis and tumorigenesis. Mol Cell Biol. 2006 Apr; 26(8):2877-86.
Wilhelmsen K, Litjens SH, Kuikman I, Tshimbalanga N, Janssen H, van den Bout I, Raymond K, Sonnenberg A. Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin. J Cell Biol. 2005 Dec 5; 171(5):799-810.
Litjens SH, Wilhelmsen K, de Pereda JM, Perrakis A, Sonnenberg A. Modeling and experimental validation of the binary complex of the plectin actin-binding domain and the first pair of fibronectin type III (FNIII) domains of the beta4 integrin. J Biol Chem. 2005 Jun 10; 280(23):22270-7.
Wilhelmsen K, Copp J, Glenn G, Hoffman RC, Tucker P, van der Geer P. Purification and identification of protein-tyrosine kinase-binding proteins using synthetic phosphopeptides as affinity reagents. Mol Cell Proteomics. 2004 Sep; 3(9):887-95.
Wilhelmsen K, van der Geer P. Phorbol 12-myristate 13-acetate-induced release of the colony-stimulating factor 1 receptor cytoplasmic domain into the cytosol involves two separate cleavage events. Mol Cell Biol. 2004 Jan; 24(1):454-64.
Wilhelmsen K, Burkhalter S, van der Geer P. C-Cbl binds the CSF-1 receptor at tyrosine 973, a novel phosphorylation site in the receptor's carboxy-terminus. Oncogene. 2002 Feb 7; 21(7):1079-89.