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William Muller, MD, PhD
Magerstadt Professor and Chairman of Pathology
Ward 3-140
303 E. Chicago Avenue
Chicago, IL 60611
wamuller@northwestern.edu
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Phone: (312) 503-8144
Fax: (312) 503-8249
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Anatomic Pathology Division
Autopsy
Medical School
Cornell University Medical College
/ The Rockefeller University (PhD)
Site of Residency
Massachusetts General Hospital
/ Brigham and Women's Hospital
Research Interests
My research group is studying the molecular and cellular basis for homing of leukocytes to sites of inflammation. In particular, we study the biology of adhesion molecules responsible for the binding and emigration of leukocytes across vascular endothelial cells. These adhesion events are crucial to the processes of inflammation and atherosclerosis, as well as to both the afferent and efferent arms of acquired immunity.
We have identified and cloned PECAM-1, a molecule that is required for transendothelial migration of leukocytes. We have also cloned VE-Cadherin, an endothelial-specific cadherin that may play a regulatory role in leukocyte emigration. Most recently, we have identified CD99 and the related molecule CD99L2 as molecules concentrated at endothelial cell borders and on the surfaces of leukocytes that also play critical roles in transendothelial migration that are distinct from that of PECAM. The roles of these adhesion molecules are being tested using both in vitro and in vivo models.
We have demonstrated that anti-PECAM monoclonal antibodies or soluble recombinant PECAM blocks inflammation in several models of acute inflammation. Likewise, blocking the function of CD99 or CD99L2 inhibits leukocyte egress into a site of inflammation, as predicted by our in vitro assays. In order to study the role of these molecules in chronic inflammatory states such as multiple sclerosis, arthritis, and atherosclerosis, we are using mice in which these molecules have been genetically deleted (knockout mice).
We have discovered a novel membrane organelle in endothelial cells, the lateral border recycling compartment (LBRC) that is critical for leukocyte transendothelial migration (Nature, 421:748, 2003). This reticulum of interconnected vesicles contains PECAM, CD99, and other molecules important for leukocyte transmigration, but excludes other structural components of the endothelial junction. When the leukocyte reaches the endothelial cell border, the LBRC is targeted to surround the leukocyte as it crosses the endothelial junction. This targeted trafficking is mediated by kinesin molecular motors and requires intact microtubules. Targeted trafficking of the LBRC is required for leukocyte diapedesis of all classes of leukocytes. If we interrupt it by depolymerizing microtubules or inhibiting kinesin, we block leukocyte migration and arrest leukocytes over the endothelial border, just as we do if we directly inhibited PECAM. We hypothesize that PECAM-PECAM interactions at the apical surface of the cell send a signal that recruits the LBRC. Current research is directed at identifying the signaling pathway for LBRC recruitment.
More recently, we have shown that under conditions where leukocytes migrate through the endothelial cell rather than at the cell borders, the LBRC is also involved. The membrane traffics from its normal location along the cell junction to the site where the leukocyte is migrating and invests it with a channel lined with the appropriate junctional adhesion molecules. Thus, migration of leukocytes through endothelial cells and between endothelial cells involves the same mechanisms. The sine qua non of leukocyte emigration is recruitment of the LBRC. This is a new paradigm in inflammation. In ongoing research we are attempting to isolate and purify the LBRC membranes in order to objectively analyze their protein and lipid components. We hope that studies of the LBRC will lead to selective inhibitors of targeted trafficking and thus, to potential anti-inflammatory therapeutics.
In addition to intracellular signaling involved in LBRC recruitment, we are looking at intercellular signaling, or "cross-talk" between leukocytes and endothelial cells during inflammation. Leukocyte-endothelial cell interactions influence the subsequent phenotype and physiology of both cell types and are important determinants in the outcome of the inflammatory response.
Selected Publications
Lou O, Alcaide P, Luscinskas FW, Muller WA. CD99 is a key mediator of the transendothelial migration of neutrophils.
J Immunol. 2007 Jan 15;178(2):1136-43.
Reinke EK, Lee J, Zozulya A, Karman J, Muller WA, Sandor M, Fabry Z. Short-term sPECAM-Fc treatment ameliorates EAE while chronic use hastens onset of symptoms. J Neuroimmunology 186:86-93, 2007
Schenkel AR, Dufour EM, Chew TW, Sorg E, Muller WA. The murine CD99-related molecule CD99-like 2 (CD99L2) is an adhesion molecule involved in the inflammatory response. Cell Commun Adhes 14:227-237, 2007
Mamdouh Z, Kreitzer GE, Muller WA. Leukocyte transmigration requires kinesin-mediated microtubule-dependent membrane trafficking from the Lateral Border Recycling Compartment. J Exp Med 205:951-966, 2008
Dufour EM, DeRoche A, Bae Y, Muller WA. CD99 is essential for leukocyte diapedesis in vivo. Cell Commun Adhes 16:1-13, 2008.
Dasgupta B, Muller WA. Endothelial Src kinase regulates membrane recycling from the Lateral Border Recycling Compartment (LBRC) during leukocyte transendothelial migration (TEM). Eur J Immunol 38:1-9, 2008.
View more Publications by William Muller, MD, PhD
listed in the National Library of Medicine (PubMed)
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