RESUMEN
Human parvovirus B19 (B19V) is a single-stranded non-enveloped DNA virus of the family Parvoviridae that has been associated with various autoimmune disorders. Systemic sclerosis (SSc) is an autoimmune connective tissue disorder with high mortality and has been linked to B19V infection. However, the precise mechanism underlying the B19V contribution to the development of SSc remains uncertain. This study investigated the impacts of the functional B19V-VP1 unique region (VP1u) in macrophages and bleomycin (BLE)-induced SSc mice. Cell experimental data showed that significantly decreased viability and migration of both B19V-VP1u-treated U937 and THP-1 macrophages are detected in the presence of celastrol. Significantly increased MMP9 activity and elevated NF-kB, MMP9, IL-6, TNF-α, and IL-1ß expressions were detected in both B19V-VP1u-treated U937 and THP-1 macrophages. Conversely, celastrol revealed an inhibitory effect on these molecules. Notably, celastrol intervened in this pathogenic process by suppressing the sPLA2 activity of B19V-VP1u and subsequently reducing the inflammatory response. Notably, the administration of B19V-VP1u exacerbated BLE-induced skin fibrosis in mice, with augmented expressions of TGF-ß, IL-6, IL-17A, IL-18, and TNF-α, ultimately leading to α-SMA and collagen I deposits in the dermal regions of BLE-induced SSc mice. Altogether, this study sheds light on parvovirus B19 VP1u linked to scleroderma and aggravated dermal fibrosis.
Asunto(s)
Infecciones por Parvoviridae , Parvovirus B19 Humano , Esclerodermia Sistémica , Animales , Humanos , Ratones , Proteínas de la Cápside/genética , Fibrosis , Interleucina-6/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Infecciones por Parvoviridae/complicaciones , Parvovirus B19 Humano/genética , Esclerodermia Sistémica/inducido químicamente , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas ViralesRESUMEN
Human parvovirus B19 (B19V) has been strongly associated with a variety of inflammatory disorders, such as rheumatoid arthritis (RA), inflammatory bowel disease and systemic lupus erythematosus. Nonstructural protein 1 (NS1) of B19V has been demonstrated to play essential roles in the pathological processes of B19V infection due to its regulatory properties on inflammatory cytokines. Celastrol, a quinone methide isolated from Tripterygium wilfordii, has displayed substantial potential in treating inflammatory diseases, such as psoriasis and RA. However, little is known about the effects of celastrol on B19V NS1induced inflammation. Therefore, cell viability assay, migration assay, phagocytosis analysis, zymography assay, ELISA and immunoblotting were conducted to verify the influences of celastrol on macrophages. The present study reported the attenuating effects of celastrol on B19V NS1induced inflammatory responses in macrophages derived from human acute monocytic leukemia cell lines, U937 and THP1. Although the migration was not significantly decreased by celastrol in both U937 and THP1 macrophages, significantly decreased viability, migration and phagocytosis were detected in both B19V NS1activated U937 and THP1 macrophages in the presence of celastrol. Additionally, celastrol significantly decreased MMP9 activity and the levels of inflammatory cytokines, including IL6, TNFα and IL1ß, in B19V NS1activated U937 and THP1 cells. Notably, significantly decreased levels of NLR family pyrin domaincontaining 3, apoptosisassociated specklike, caspase1 and IL18 proteins were observed in both B19V NS1activated U937 and THP1 cells in the presence of celastrol, indicating the involvement of the inflammasome pathway. To the best of our knowledge, the present study is the first to report on the attenuating effects of celastrol on B19V NS1induced inflammatory responses in macrophages, suggesting a therapeutic role for celastrol in B19V NS1related inflammatory diseases.