Cutting Edge: Bacterial Lipoprotein Induces Endotoxin-Independent Tolerance to Septic Shock

Abstract

Tolerance to bacterial cell wall components is an adaptive host response. Endotoxin/LPS tolerance is characterized by a survival advantage against subsequent lethal LPS challenge. However, it is uncertain whether LPS tolerance can afford protection against other septic challenges. In this study, we show that tolerance induced by bacterial lipoprotein (BLP) protects mice against not only BLP-induced lethality, but also LPS-, live bacteria-, and polymicrobial sepsis-induced lethality. In contrast, LPS tolerance offers no survival benefit against the latter two challenges. Furthermore, induction of BLP tolerance results in overexpression of complement receptor type 3 and FcγIII/IIR on neutrophils (polymorphonuclear neutrophils) and peritoneal macrophages, with increased bacterial recognition and bactericidal activity, whereas LPS-tolerized mice exhibit an impaired ability to ingest and to kill bacteria. These results indicate that BLP tolerance is a novel adaptive host response associated with a unique protective effect during septic shock.

The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll‐like receptor‐mediated inflammatory signals

“…In support of this hypothesis, endotoxin or LPS tolerance is a well-established phenomenon in which pre-exposure to a sublethal dose of LPS blunts subsequent lethal LPS-induced mortality, and this effect was closely associated with diminished production of proinflammatory cytokines [34,35]. In addition to LPS tolerance, several non-LPS bacterial cell wall components, including bacterial lipoprotein (BLP), also induce tolerance [36,37]. Unlike LPS or BLP, however, ginsan exhibited a wide spectrum of bacterial tolerance in Gram-positive, Gram-negative, and polymicrobial septic models and did not induce lethal shock, even at high concentrations.…”

Differential effects of CpG‐DNA in Toll‐like receptor‐2/‐4/‐9 tolerance and cross‐tolerance

“…8,[10][11][12] In light of the finding that 10 cellular responses to different microbial stimuli are mediated by different 11 TLRs, studies were initiated to determine whether, in analogy to LPS tolerance, pretreatment with microbial non-LPS stimuli also induces hyporesponsiveness to subsequent restimulation. Indeed, it has been reported that stimulation with prototypical ligands for TLR-2 (+TLR-1 or -6), [13][14][15][16][17][18] TLR-4, TLR-5 19 and TLR-9 20,21 also induces this state of hyporesponsiveness towards subsequent stimulation with the same ligand. Moreover, stimuli signalling via TLR-2 and TLR-4, 14,15 as well as TLR-4 and TLR-9, 20 can substitute for each other, mediating cross-tolerance in vitro as well as in vivo.…”

ST2 Negatively Regulates TLR2 Signaling, but Is Not Required for Bacterial Lipoprotein-Induced Tolerance

“…Our in vivo work demonstrated that pretreatment with a nonlethal dose of BLP protects mice against not only a subsequent lethal BLP challenge, but also a subsequent lethal LPS challenge through a cross-tolerance to LPS (8). Unlike LPS tolerance, BLP tolerance-afforded protection against microbial sepsis was observed in both wild-type (WT) (8) and TLR4-deficient (9) mice.…”

“…Our in vivo work demonstrated that pretreatment with a nonlethal dose of BLP protects mice against not only a subsequent lethal BLP challenge, but also a subsequent lethal LPS challenge through a cross-tolerance to LPS (8). Unlike LPS tolerance, BLP tolerance-afforded protection against microbial sepsis was observed in both wild-type (WT) (8) and TLR4-deficient (9) mice. This is closely associated with BLP-induced reprogramming in phagocytes characterized by hypo-responsiveness in producing proinflammatory cytokines and simultaneously an enhanced antimicrobial activity (7)(8)(9).…”