# Transendothelial Migration of Leukocytes:  Developing New Paradigms in Health and Disease

> **NIH NIH R35** · NORTHWESTERN UNIVERSITY · 2021 · $848,469

## Abstract

Project Summary/Abstract
 Transendothelial migration (TEM), or diapedesis, is the step in which leukocytes squeeze between tightly
apposed endothelial cells that line the post-capillary venules at sites of inflammation. Most of the good, the bad,
and the ugly of inflammation occurs after leukocytes cross blood vessels. A thorough understanding of the
molecules and mechanisms that regulate TEM should therefore enhance our ability to control the process
therapeutically. Therefore, my lab has been studying this process for 30 years. We have made some of the
seminal discoveries in the field, including the identification and discovery of: 1.Platelet/endothelial cell adhesion
molecule-1 (PECAM) and CD99 as major selective regulators of TEM and 2. their downstream signaling
pathways leading to TEM; 3.The lateral border recycling compartment (LBRC), an interconnected reticulum of
tubule-vesicular membrane that recycles locally along the endothelial cell borders; 4.That the surface molecules
involved in TEM (PECAM, CD99, etc.) work sequentially in the process as the leukocyte passes through the
endothelial cell border; 5.That the act of TEM promotes differentiation of some monocytes into dendritic cells; 6.
That paracellular and transcellular TEM of leukocytes use the same machinery and mechanisms.
 Whether we approached TEM from the standpoint of the leukocyte or the endothelial cell, the surface
adhesion/signaling molecules, the intracellular signaling pathways, membrane dynamics, or endothelial cell
ultrastructure, we consistently and independently converged on a final common mechanism regardless of
whether we were studying neutrophils, monocytes, or T cells; regardless of the inflammatory conditions or
models studied: TEM required the targeted movement of the LBRC along microtubules to the site at which the
leukocyte was migrating. All of the molecules that we studied worked to activate this mechanism. Anything that
inhibited this “targeted recycling of the LBRC” inhibited TEM by 80-90% in vitro and in vivo.
 The biggest shortcoming of existing anti-inflammatory therapies is that they also block beneficial
inflammation. We have developed biochemical and genetic tools to selectively block targeted recycling of the
LBRC and hence TEM in multiple in vivo models of inflammatory disease. Since these reagents and inducible
EC-selective knockout mice only affect EC, all other aspects of the innate and adaptive inflammatory responses
remain intact. Since we are only able to block TEM by 80–90%, the 10–20% of leukocytes that escape blockade
enter the tissues able to mount a normal inflammatory response. Our preliminary data show that we can diminish
the intensity of maladaptive inflammation without interfering with the ability of the host to mount desirable
inflammatory responses and remain healthy. We will test this hypothesis in a number of models of acute and
chronic inflammation. We will also use our ability to selective block TEM at selected time points t...

## Key facts

- **NIH application ID:** 10108156
- **Project number:** 1R35HL155652-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** William A Muller
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $848,469
- **Award type:** 1
- **Project period:** 2021-03-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10108156

## Citation

> US National Institutes of Health, RePORTER application 10108156, Transendothelial Migration of Leukocytes:  Developing New Paradigms in Health and Disease (1R35HL155652-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10108156. Licensed CC0.

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