Increased TLR4 Expression Aggravates Sepsis by Promoting IFN-γExpression in CD38^−/−Mice

Abstract

Gram-negative bacterial sepsis accounts for up to 50% worldwide sepsis that causes hospital mortality. Acute kidney injury (AKI), a common complication of Gram-negative bacterial sepsis, is caused by Toll-like receptor 4 (TLR4) activation. Lipopolysaccharide (LPS) is an endotoxin in Gram-negative bacteria and is recognized specifically by TLR4, which initiates innate immune response. Also, TLR4 signaling pathway activation is essential in response to LPS infection. CD38 is one of the well-known regulators of innate immunity, whose dysregulation contributes to sepsis. Many studies have proven that an attenuated Gram-positive bacterium induces sepsis in a CD38-blocking model. However, the pathogenesis of Gram-negative bacteria-induced sepsis in a CD38−/− mouse model remains unclear. The aim of this study is to investigate whether kidney injury is still attenuated in a LPS-induced CD38−/− sepsis model and identify the potential mechanism. We assess the severity of kidney injury related to proinflammatory cytokine expressions (IFN-γ, TNF-α, IL-1β, and IL-6) in WT and CD38−/− mice. Our results showed more aggravated kidney damage in CD38−/− mice than in WT mice, accompanied with an increase of proinflammatory cytokine expression. In addition, compared with CD38−/−TLR4mut mice, we found an increase of TLR4 expression and mRNA expression of these cytokines in the kidney of CD38−/− mice, although only increased IFN-γ level was detected in the serum. Taken together, these results demonstrated that an increased TLR4 expression in CD38−/− mice could contribute to the aggravation of AKI through boosting of the production of IFN-γ.

Roles of CD38 in the Immune Response to Infection

“…In line with the role of CD38 in maintenance of a pro-inflammatory phenotype, macrophages that had recovered from quercetin-treated mice had lower levels of NF-kB signaling and inflammatory markers as compared to macrophages from vehicle-treated mice [36]. Flavonoids, however, may also use protective mechanisms that are independent of CD38 inhibition, as the contributing role of CD38 in tissue damage was not confirmed in CD38-deficient mice [76]. CD38 deficiency aggravated kidney injury upon LPS-induced sepsis, in correlation with increased expression of Toll-like receptor (TLR)4 in the kidney and pro-inflammatory cytokine production.…”

CD38: An Immunomodulatory Molecule in Inflammation and Autoimmunity

“…However, the contribution of CD38 towards cytokine release is still controversial since opposite behaviors have been reported in mouse cells. For instance, CD38 deficient mice had increased levels of TLR4 expression in kidney and enhanced secretion of IL-1b, IL-6, IFN-g, and TNF-a during kidney injury induced by LPS challenge (90). Moreover, CD38 deficiency in unstimulated Raw264.7 mouse macrophages suppressed expression of TLR2 through deacetylation of NF-kB by Sirtuin (SIRT) 1 in an NAD-dependent manner.…”

TLR4-NLRP3-GSDMD-Mediated Pyroptosis Plays an Important Role in Aggravated Liver Injury of CD38-/- Sepsis Mice

“…It has been reported that CD38 deletion can activate NF- κ B and the expression of downstream inflammatory factors to aggravate the inflammatory response [ 12 ], and this pathway is related to TLR4 [ 48 ]. Takayashiki et al showed that increased expression of TLR4 enhances endotoxin-induced hepatic failure [ 49 ], and our previous studies have shown that CD38 deficiency enhances TLR4 expression in the kidneys of LPS-induced septic mice [ 50 ]. In line with these, in this study, we also found that CD38 deletion can upregulate TLR4 expression, induce phosphorylation of downstream NF- κ B p65, and activate the expression of downstream inflammatory factors and apoptosis gene in an E. coli -induced liver injury model, and TLR4 mutation significantly rescues the liver injury from inflammatory response aggravated by CD38 deficiency.…”