# LPS Signaling in Macrophages: The Roll of Toll

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $986,460

## Abstract

The innate immune system is the first line of defense against pathogens. Innate immune cells lack the
exquisite specificity of the adaptive immune system, yet in order to respond in a measured way, they must be
able to tailor their activity to the specific pathogen. These cells have therefore evolved pattern recognition
receptors (PRRs) that recognize conserved molecules characteristic of the microbe, which are not found within
the host. The Toll-like receptors (TLRs) are the archetypal PRRs. The innate immune response to viruses
occurs principally by inducing type I interferons (IFN). It has recently been appreciated that IFN also functions
in the response to bacteria, although its role here is poorly defined. We have shown that 25-HC, an oxysterol
which is derived enzymatically from cholesterol by Ch25h, has a role in regulating the inflammatory response
and immunity. Ch25h is strongly induced by both TLR2-activation and by IFN, and we have further
demonstrated that 25-HC reciprocally impacts both of these pathways: It amplifies and sustains a subset of the
TLR-induced inflammatory genes while simultaneously suppressing expression of a subset of interferon-
stimulated genes. Therefore, Ch25h is an immune modulator situated at the intersection of these two major
pathways, the precise regulation of which is crucial to controlling viral and bacterial infections such as Listeria
monocytogenes and Mycobacterium tuberculosis. We propose to identify the molecular mechanisms by which
25-HC impacts TLR and IFN responses and determine the role of these interactions in control of bacterial
infections. We will first define the mechanism by which 25-HC amplifies TLR2 signaling in macrophages by
examining the mechanism by which 25-HC suppresses IL-10 production and determining the role of 25-HC-
mediated epigenetic regulation in altering expression of TLR2 induced genes. Next we will determine the
mechanisms by which 25-HC regulates crosstalk between interferon and inflammatory signaling. Here we
shall determine the mechanism by which 25-HC mediates the suppression of IFN-stimulated genes. We shall
then determine the role of 25-HC in cross-regulation between innate immune pathways. Finally, we will
determine the role of 25-HC in macrophage control of Listeria monocytogenes in vitro and in vivo.

## Key facts

- **NIH application ID:** 9966843
- **Project number:** 5R01AI032972-31
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** ALAN A ADEREM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $986,460
- **Award type:** 5
- **Project period:** 2022-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966843

## Citation

> US National Institutes of Health, RePORTER application 9966843, LPS Signaling in Macrophages: The Roll of Toll (5R01AI032972-31). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9966843. Licensed CC0.

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