Macrophage-Derived CCL20 Promotes Abdominal Aortic Aneurysm Progression Via Lymphocytes CCR6

Qingnan Ren^1,2Sun Tianyong²Song Shen²Yuanbin Cao¹Li Wei²Yang Zhao¹Fengxin Wan¹Ping Sui¹Ke Xiao³Hao Bai⁴Dachuan Guo⁵Qi He²Mengfan Zhi⁶Jianmin Yang⁷Jianjun Jiang¹Wencheng Zhang^5*Xiangjiu Ding^1,7*

• ¹Qilu Hospital of Shandong University Department of Vascular Surgery, Jinan, China
• ²Department of Health Care (Department of General Dentistry Ⅱ), Human Microbiome, Shandong Key Laboratory of Oral Tissue Regeneration, Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration, Shandong Provincial Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Shandong University School of Stomatology, Jinan, China
• ³Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
• ⁴Clinical Epidemiology Unit, Department of Nutrition, Clinical Research Center of Shandong University, Qilu Hospital of Shandong University, Jinan, China
• ⁵State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
• ⁶Department of Health Care (Department of General Dentistry Ⅱ), Human Microbiome, Shandong Key Laboratory of Oral Tissue Regeneration, Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration, Shandong Provincial Clinical Research Center for Oral Diseases, Shandong University School of Stomatology, Jinan, China
• ⁷Shandong Key Laboratory of Medicine and Prevention Integration in Rheumatism and Immunity Disease, Qilu Hospital of Shandong University, Jinan, China

Introduction: Abdominal aortic aneurysm (AAA) is a chronic vascular disease marked by chronic inflammation and immune dysregulation. The C-C motif chemokine ligand 20 (CCL20) - C-C motif chemokine receptor type 6 (CCR6) axis modulates immune responses in vascular diseases, but its role in AAA remains unclear. This study investigates the involvement of the CCL20-CCR6 axis in AAA formation. Methods: Single-cell RNA sequencing datasets and bulk RNA sequencing datasets were analyzed to assess cellular composition and transcriptional changes. Transcriptomic analysis, enzyme-linked immunosorbent assay, UK Biobank database analysis, CellChat analysis, immunofluorescence staining, and mouse models were employed to explore the CCL20-CCR6 axis in AAA. Results: Substantial immune cell infiltration (T lymphocytes & B lymphocytes) and loss of structural cells (fibroblasts, endothelial cells and smooth muscle cells) were identified using single-cell RNA sequencing datasets. Macrophage polarization was imbalanced, with enriched M1-like macrophages and elevated CCL20 secretion. Macrophages could promote the formation of AAA by recruiting a large number of immune cells via the CCL20-CCR6 axis. In vitro, CCL20 neutralization reduced immune cell recruitment; in vivo, the knockdown of this axis inhibited AAA progression. Conclusions: Macrophage-derived CCL20 aggravates lymphocyte recruitment via the CCR6, promoting AAA progression. CCL20 may serve as a biomarker for AAA. Targeting the CCL20-CCR6 axis could inhibit immune recruitment and AAA progression.