Induction of Interferon‐γ and Tissue Inflammation by Overexpression of Eosinophil Cationic Protein in T Cells and Exosomes

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 74; no. 1; pp. 92 - 104
• Main Authors: Chuang, Huai‐Chia, Chen, Ming‐Han, Chen, Yi‐Ming, Ciou, Yi‐Ru, Hsueh, Chia‐Hsin, Tsai, Ching‐Yi, Tan, Tse‐Hua
• Format: Journal Article
• Language: English
• Published: Boston, USA Wiley Periodicals, Inc 01.01.2022; Wiley Subscription Services, Inc
• Subjects: Animals; Arthritis; Autoantibodies; Autoimmune diseases; Biomarkers; Cations; Chronic conditions; Eosinophil cationic protein; Eosinophil Cationic Protein - biosynthesis; Exosomes; Exosomes - immunology; Full Length; Gene sequencing; Hepatitis; Humans; Inflammation; Inflammation - immunology; Interferon; Interferon-gamma - immunology; Leukocytes (eosinophilic); Lupus Erythematosus, Systemic - immunology; Lymphocytes; Lymphocytes T; Mice; Mice, Transgenic; mRNA; Nephritis; Pathogenesis; Proteins; Proteomics; Ribonuclease III; Rodents; Systemic Lupus Erythematosus; T-Lymphocytes - immunology; Tissues; Transgenic animals; Transgenic mice; γ-Interferon
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.41920

Objective T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Serum‐derived exosomes are increased in SLE patients and are correlated with disease severity. This study was undertaken to investigate whether T cell–derived exosomal proteins play a role in SLE pathogenesis. Methods We characterized proteins in T cell–derived exosomes from SLE patients and healthy controls by MACSPlex exosome analysis and proteomics. To study the potential pathogenic functions of the exosomal protein identified, we generated and characterized T cell–specific transgenic mice that overexpressed that protein in T cells. Results We identified eosinophil cationic protein (ECP, also called human RNase III) as overexpressed in SLE T cell–derived exosomes. T cell–specific ECP–transgenic mice (n = 5 per group) displayed early induction of serum interferon‐γ (IFNγ) levels (P = 0.062) and inflammation of multiple tissue types. Older T cell–specific ECP–transgenic mice (n = 3 per group) also displayed an increase in follicular helper T cell and plasma B cell numbers, and in autoantibody levels (P < 0.01). Single‐cell RNA sequencing showed the induction of IFNγ messenger RNA (P = 2.2 × 10‐13) and inflammatory pathways in ECP‐transgenic mouse T cells. Notably, adoptively transferred ECP‐containing exosomes stimulated serum autoantibody levels (P < 0.01) and tissue IFNγ levels in the recipient mice (n = 3 per group). The transferred exosomes infiltrated into multiple tissues of the recipient mice, resulting in hepatitis, nephritis, and arthritis. Conclusion Our findings indicate that ECP overexpression in T cells or T cell–derived exosomes may be a biomarker and pathogenic factor for nephritis, hepatitis, and arthritis associated with SLE.