# Regulating Leukocyte Migration in Inflammation

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $402,500

## Abstract

The overall objective of our research program is to understand how leukocytes migrate into
inflamed tissues so that new therapeutic strategies can be developed to treat inflammatory
diseases. One of the fundamental processes of inflammation is the directed migration of
leukocytes into target organs following a gradient of chemokines or pathogen products, a process
called chemotaxis. Blocking chemotaxis alone is effective for treating human inflammatory
diseases. However, how leukocytes sense and follow chemical gradients is not well understood.
This application is inspired by our recent discovery that leukocytes deficient in the TIPE (tumor
necrosis factor-a-induced protein 8-like) family of proteins are “compassless”, and non-
polarizable: they are unable to polarize or migrate towards chemoattractants or into nervous
tissue to cause inflammation despite their normal motility. The TIPE family are “professional”
transfer proteins of the phospholipid second messengers PIP2 and PIP3, and risk factors for both
inflammation and cancer. We initially cloned the TIPE2 gene from the spinal cord of mice with
autoimmune encephalomyelitis and found that it was preferentially expressed by leukocytes. We
then generated TIPE2-deficient mice and found that they were significantly resistant to neural
inflammation. Unexpectedly, TIPE2-deficient leukocytes have no defects in motility or activation,
but are severely compromised in their directionality, i.e., the ability to sense and follow the gradient
of chemoattractants. We therefore propose that the TIPE family is the long-sought-after compass
of leukocytes that confers polarity and directionality during inflammation. In this proposal, we will
test the hypotheses that TIPE proteins (i) direct leukocytes into nervous tissue during
inflammation and (ii) polarize leukocytes through the mechanism of local excitation and global
inhibition.

## Key facts

- **NIH application ID:** 10058241
- **Project number:** 5R01AI136945-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Honghong Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2017-12-22 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058241

## Citation

> US National Institutes of Health, RePORTER application 10058241, Regulating Leukocyte Migration in Inflammation (5R01AI136945-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10058241. Licensed CC0.

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