RESUMO
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vasculopathy. CXCL4 represents an early serum biomarker of severe SSc and likely contributes to inflammation via chemokine signaling pathways, but the exact role of CXCL4 in SSc pathogenesis is unclear. Here, we elucidate an unanticipated mechanism for CXCL4-mediated immune amplification in SSc, in which CXCL4 organizes "self" and microbial DNA into liquid crystalline immune complexes that amplify TLR9-mediated plasmacytoid dendritic cell (pDC)-hyperactivation and interferon-α production. Surprisingly, this activity does not require CXCR3, the CXCL4 receptor. Importantly, we find that CXCL4-DNA complexes are present in vivo and correlate with type I interferon (IFN-I) in SSc blood, and that CXCL4-positive skin pDCs coexpress IFN-I-related genes. Thus, we establish a direct link between CXCL4 overexpression and the IFN-I-gene signature in SSc and outline a paradigm in which chemokines can drastically modulate innate immune receptors without being direct agonists.
Assuntos
DNA Bacteriano/metabolismo , Interferon-alfa/metabolismo , Fator Plaquetário 4/metabolismo , Escleroderma Sistêmico/imunologia , Receptor Toll-Like 9/metabolismo , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , DNA Bacteriano/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Interferon-alfa/imunologia , Cristais Líquidos , Masculino , Pessoa de Meia-Idade , Fator Plaquetário 4/imunologia , Receptores CXCR3/imunologia , Receptores CXCR3/metabolismo , Escleroderma Sistêmico/microbiologia , Escleroderma Sistêmico/patologia , Pele/citologia , Pele/imunologia , Pele/microbiologia , Pele/patologia , Receptor Toll-Like 9/imunologiaRESUMO
The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death1,2; however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defined. Here we use mouse models of atherosclerosis-a major underlying cause of mortality worldwide-to demonstrate that extracellular histone H4-mediated membrane lysis of smooth muscle cells (SMCs) triggers arterial tissue damage and inflammation. We show that activated lesional SMCs attract neutrophils, triggering the ejection of neutrophil extracellular traps that contain nuclear proteins. Among them, histone H4 binds to and lyses SMCs, leading to the destabilization of plaques; conversely, the neutralization of histone H4 prevents cell death of SMCs and stabilizes atherosclerotic lesions. Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.
