# Modulation of Chronic Th2 inflammation by the CCR8 Receptor-Ligand Pathway

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $416,850

## Abstract

Summary
Regulators of Th2 inflammation at the barrier interface in chronic allergic diseases such as atopic
dermatitis and asthma are not as well characterized as those in the initiation phase. Yet effector functions
of leukocytes in the chronic phase of Th2 inflammation drive symptomatic human disease that results in
immune pathology associated with much morbidity after usually asymptomatic allergen sensitization.
Chemokines are chemotactic cytokines that control leukocyte recruitment and inflammation by binding
specific receptors on target cells. We recently discovered that the human chemokine CCL18 is a novel
agonist of the CCR8 receptor. CCL18 is a signature chemokine produced by Th2 cytokine differentiated
IL-4 spectrum macrophages, M(IL-4)s, also known as alternatively activated or M2 macrophages.
CCL18 is associated with several chronic and eosinophilic inflammatory human diseases, and is one of
the most highly induced chemokines in lesional atopic dermatitis skin. M(IL-4) interactions with the
recently discovered Group 2 Innate Lymphoid Cells (ILC2) have been shown to facilitate eosinophilic
inflammation. CCR8 is also a top signature gene of the mouse ILC2 transcriptome. Recently IL-4Rα
blockade, which inhibits M(IL-4) differentiation, resulted in striking clinical improvement of treatment
refractory atopic dermatitis that highly correlated with suppression of CCL18. Yet, whether and how
CCL18 and M(IL-4)s sustain chronic atopic dermatitis pathology is not known. Our published and new
preliminary data lead us to hypothesize that though M(IL-4)s are anti-inflammatory in acute inflammation,
they undergo pathogenic transformation at barrier interfaces to become pro-inflammatory in chronic
inflammation, and partly through the CCR8 pathway and other mediators, and local interactions with cells
such as ILC2s sustain chronic eosinophilic allergic inflammation in the skin. To test this hypothesis we will
use a model of chronic allergic dermatitis. We also discovered a novel mouse chemokine agonist of the
CCR8 receptor that is a functional analog of CCL18. We thus propose to: (1) Determine if M(IL-4)s are
crucial for chronic allergic inflammation and identify mechanisms by which they do so, and if this is
regulated by the CCR8 pathway; and (2) Define how ILC2s contribute to chronic allergic inflammation and
if this is mediated by the CCR8 pathway. We will determine the clinical correlates of the studies proposed
in Aims 1 and 2 using clinical specimens from individuals with eczema that will be compared to healthy
controls.

## Key facts

- **NIH application ID:** 10055847
- **Project number:** 5R01AI121248-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** SABINA A ISLAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $416,850
- **Award type:** 5
- **Project period:** 2016-11-21 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055847

## Citation

> US National Institutes of Health, RePORTER application 10055847, Modulation of Chronic Th2 inflammation by the CCR8 Receptor-Ligand Pathway (5R01AI121248-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10055847. Licensed CC0.

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