Pathogenic Tconvs promote inflammatory macrophage polarization through GM-CSF and exacerbate abdominal aortic aneurysm formation.

Abstract

Abdominal aortic aneurysms (AAAs) elicit massive inflammatory leukocyte recruitment to the aorta. CD4+ T cells, which include regulatory T cells (Tregs) and conventional T cells (Tconvs), are involved in the progression of AAA. Tregs have been reported to limit AAA formation. However, the function and phenotype of the Tconvs found in AAAs remain poorly understood. We characterized aortic Tconvs by bulk RNA sequencing and discovered that Tconvs in aortic aneurysm highly expressed Cxcr6 and Csf2. Herein, we determined that the CXCR6/CXCL16 signaling axis controlled the recruitment of Tconvs to aortic aneurysms. Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF), encoded by Csf2, markedly inhibited AAA formation and led to a decrease of inflammatory monocytes, due to a reduction of CCL2 expression. Conversely, the exogenous administration of GM-CSF exacerbated inflammatory monocyte infiltration by upregulating CCL2 expression, resulting in worsened AAA formation. Mechanistically, GM-CSF upregulated the expression of interferon regulatory factor 5 to promote M1-like macrophage differentiation in aortic aneurysms. Importantly, we also demonstrated that the GM-CSF produced by Tconvs enhanced the polarization of M1-like macrophages and exacerbated AAA formation. Our findings revealed that GM-CSF, which was predominantly derived from Tconvs in aortic aneurysms, played a pathogenic role in the progression of AAAs and may represent a potential target for AAA treatment.

• Authors: Dan Li, Jingyong Li, Henan Liu, Luna Zhai, Wangling Hu, Ni Xia, Tingting Tang, Jiao Jiao, Bingjie Lv, Shaofang Nie, Desheng Hu, Yuhua Liao, Xiangping Yang, Guo-Ping Shi, Xiang Cheng
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 36 Issue 3 Pg. e22172 (03 2022) ISSN: 1530-6860 [Electronic] United States
• PMID: 35133017 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Interferon Regulatory Factors
• Irf5 protein, mouse
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Aortic Aneurysm, Abdominal (metabolism)
• Cell Differentiation
• Cells, Cultured
• Chemokine CCL2 (genetics, metabolism)
• Granulocyte-Macrophage Colony-Stimulating Factor (genetics, metabolism)
• Interferon Regulatory Factors (genetics, metabolism)
• Macrophages (cytology, immunology)
• Male
• Mice
• Mice, Inbred C57BL
• T-Lymphocytes (immunology)