Abstract
Monocyte apoptosis is a key mechanism that orchestrates host immune responses during sepsis. TRIM22 is constitutively expressed at high levels in monocytes and plays important roles in the antiviral response and inflammation. Overexpression of TRIM22 interferes with the clonogenic growth of monocytic cells, suggesting that TRIM22 may regulate monocyte survival. However, the effect of TRIM22 on monocyte apoptosis remains unknown. In the present report, lipopolysaccharides (LPS)-primed human peripheral blood monocytes expressing higher levels of TRIM22 were more sensitive to apoptosis. This phenomenon was also observed in TRIM22-overexpressing THP-1 monocytes and was associated with the activation of caspase-9 and caspase-3, as well as the increased expression and oligomerization of the pro-apoptotic protein Bak. Similar expression patterns of TRIM22 and Bak were also observed in LPS-primed, apoptotic human peripheral blood monocytes. In addition, the deletion of either the RING domain or the SPRY domain of TRIM22 significantly attenuated TRIM22-mediated monocyte apoptosis and decreased Bak expression and oligomerization. Furthermore, in monocytes from septic patients, TRIM22 levels were down-regulated and positively correlated with Bak levels. Taken together, these results indicate that TRIM22 plays a critical role in monocyte apoptosis by regulating Bak oligomerization and may have a potential function in the pathogenesis of sepsis.
Highlights
Sepsis triggers a dysregulated host response to infection, which results in life-threatening organ dysfunction[1,2]
In this study, increasing the levels of both endogenous and exogenous TRIM22 sensitized monocytes to STS-induced apoptosis
This function of TRIM22 was related to the increased expression and oligomerization of Bak via a caspase-dependent pathway and was associated with the RING and SPRY domains of the TRIM22 molecule
Summary
Sepsis triggers a dysregulated host response to infection, which results in life-threatening organ dysfunction[1,2]. Monocytes are an important line of host immune defense against microbial infection They are recruited to the sites of infection, and their prolonged survival triggers immune responses and invading pathogen clearance[3,4]. It is well known that apoptosis of immune effector cells such as lymphocytes plays an important role in sepsis, but data concerning the effects of monocyte survival on sepsis are limited. It has been noted that the overexpression of TRIM22 interferes with the clonogenic growth of monocytic U937 cells[20], suggesting that it may participate in controlling monocyte survival. The effect of TRIM22 on apoptosis was first investigated in human peripheral blood monocytes and the THP-1 monocytic cell line. We measured the expression levels of TRIM22 in septic patients and analyzed the correlations between TRIM22 and apoptosis-associated proteins
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