Airway immune profiles and therapeutic implications of IGF1 in eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis (EGPA) and severe eosinophilic asthma (SEA) share a Type 2 (T2) inflammatory signature but exhibit distinct pathophysiology. We hypothesized that EGPA involves additional inflammatory mechanisms, beyond T2 immunity, that drive its systemic manifestations and treatment resistance. Using single-cell RNA sequencing, we identify interferon (IFN-I)-driven inflammation in EGPA, in contrast to TNF predominant pathway activation in SEA. IL1B<sup>+</sup>MX1<sup>+</sup> neutrophils in EGPA express IFN-stimulated genes and promote tertiary lymphoid structure formation with autoantibody production. In addition, other IFN-activated granulocytes, including APOC1<sup>+</sup> eosinophils, SCN7A<sup>+</sup> mast cells, and basophils, further contribute to immune dysregulation in EGPA, unlike TNF activated granulocytes in SEA. Longitudinal single-cell analysis of EGPA reveals an IGF1<sup>+</sup> macrophage population linked to EGPA relapse. In animal models of both conditions, IGF1 blockade attenuates T2 inflammation, mucin production, and goblet cell hyperplasia, highlighting IGF1 as a possible therapeutic target in T2 inflammation disease.
Authors
- Liuheyi Ma
- Junjie Wen
- Cong Dong (ORCID: https://orcid.org/0000-0003-1163-7966)
- Bin Lü (ORCID: https://orcid.org/0000-0002-1744-7584)
- M Mukherjee
- Q L Zhang
- Zhenan Deng (ORCID: https://orcid.org/0000-0002-8603-728X)
- Andrew M. Lew (ORCID: https://orcid.org/0000-0002-2198-8164)
- Ming Liu (ORCID: https://orcid.org/0000-0002-5987-5042)
- Xu Chen (ORCID: https://orcid.org/0000-0002-8425-036X)
- Chenyang Lu (ORCID: https://orcid.org/0000-0002-5385-7708)
- Yuxia Zhang (ORCID: https://orcid.org/0000-0003-2715-0925)
- Jianjuan Ma
- Lingna Xue
- Rongchang Chen
- Shang Wang (ORCID: https://orcid.org/0009-0001-2604-1658)
- Xiaoyu Zuo
- Changxing Ou
- Parameswaran Nair
- Lingwei Wang
- Yiyi Liu
- Changhao Zhong
- Nanshan Zhong
- Xiaojing Yang
Institutions
- Guiyang Medical University (CN)
- Jinan University (CN)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Southern University of Science and Technology (CN)
- First Affiliated Hospital of Guangzhou Medical University (CN)
- ShenZhen People’s Hospital (CN)
- Guangzhou Women and Children Medical Center (CN)
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN)
- Affiliated Hospital of Guizhou Medical University (CN)
- Guangdong Academy of Medical Sciences (CN)
- Guangdong Provincial People's Hospital (CN)
- State Key Laboratory of Respiratory Disease (CN)
- Southern Medical University (CN)
- St. Joseph’s Healthcare Hamilton (CA)
- Guangzhou Medical University (CN)
- McMaster University (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-07
- DOI
- https://doi.org/10.1038/s41467-025-68104-6
- Primary Topic
- Vasculitis and related conditions
- Type
- article
- Field-Weighted Citation Impact
- 0.00