Abstract
Tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TIPE2) is a newly discovered negative immunoregulatory protein that is involved in various cellular immune responses to infections. However, the underlying mechanism by which TIPE2 affects the immune function of dendritic cells (DCs) is not yet understood. This study aimed to determine the correlations among DCs TIPE2 expression, autophagic activity and immune function in the context of sepsis. In addition, the signaling pathway by which TIPE2 regulates autophagy in DCs was investigated. We reported for the first time that TIPE2 overexpression (knock-in, KI) exerted an inhibitory effect on autophagy in DCs and markedly suppressed the immune function of DCs upon septic challenge both in vitro and in vivo. In addition, TIPE2 knockout (KO) in DCs significantly enhanced autophagy and improved the immune response of DCs in sepsis. Of note, we found that the transforming growth factor-β (TGF-β)-activated kinase-1 (TAK1)/c-Jun N-terminal kinase (JNK) pathway was inhibited by TIPE2 in DCs, resulting in downregulated autophagic activity. Collectively, these results suggest that TIPE2 can suppress the autophagic activity of DCs by inhibiting the TAK1/JNK signaling pathway and further negatively regulate the immune function of DCs in the development of septic complications.
Highlights
Sepsis is still a nagging medical syndrome that occurs when a serious infection exceeds the host’s scavenging ability and leads to systemic inflammatory response syndrome
Dynamic alterations in autophagy in Dendritic cells (DCs) treated with lipopolysaccharide (LPS) in vitro DCs were treated with 1 μg/ml LPS for 0, 3, 6, 12, and 24 h in vitro
TIPE2 negatively regulates DC autophagy in vitro Autophagosome accumulation can be monitored by the characteristic conversion from endogenous LC3-I to LC3-II, while the inhibition of fusion between autophagosomes and lysosomes can be reflected by increased levels of p62
Summary
Sepsis is still a nagging medical syndrome that occurs when a serious infection exceeds the host’s scavenging ability and leads to systemic inflammatory response syndrome. Substantial progress in the clinical understanding and physiopathological mechanism obviously improves patient outcome, but the mortality due to sepsis is still very high, ranging from 14.7 to 29.9% [5, 9,10,11]. Dendritic cells (DCs) play pivotal roles in coordinating aberrant immunity as the link between the innate and adaptive immune systems [12, 13]. DCs are representative antigen-presenting cells that initiate the immune response by capturing, processing, and transporting antigens from somatic to secondary lymphoid tissues [14, 15]. Emerging evidence suggests that widespread DC apoptosis [16, 17] and dysfunction [12, 18,19,20] can lead to immunosuppression associated with sepsis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
