Attenuated pathogenesis of polymicrobial peritonitis in mice after TLR2 agonist pre-treatment involves ST2 up-regulation

Abstract

The innate immune system uses Toll-like receptors (TLRs) to activate and instruct immune responses against microbial pathogens. Administration of TLR agonists to mice induces a state of hyporesponsiveness, or tolerance, characterized by reduced cytokine production upon subsequent second challenge. The present study examined the effects of pre-treatment of mice with TLR2-dependent stimuli on the host defense against acute polymicrobial infection. Immune priming of mice with macrophage-activating lipopeptide-2 (MALP-2) 4 days prior to infection greatly improves survival and bacterial clearance in a model of polymicrobial septic peritonitis which is associated with enhanced accumulation of effector neutrophils in the peritoneal cavity. Further, the systemic and local production of both myeloid differentiation factor 88 (MyD88)-dependently and MyD88-independently produced cytokines was substantially diminished, but not completely absent, in TLR2-treated mice. While pre-treatment with MALP-2 does not involve differential expression of TLR and IL-1R-associated kinase proteins, ST2, a negative regulator of TLR signaling, was up-regulated after treatment of mice with either MALP-2 or N-alpha-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-L-cysteine. Therefore, ST2 may be a mechanism, among others, to attenuate the sepsis-induced cytokine burst. Thus, these results suggest that immune protection in mice after pre-treatment with TLR2-dependent stimuli involves the induction of enhanced pathogen defense by neutrophils. In addition, up-regulation of ST2 could contribute to the diminished cytokine production.

Inhibition of Interleukin-22 Attenuates Bacterial Load and Organ Failure during Acute Polymicrobial Sepsis

“…To further analyze the impact of pretreatment of mice with the IL-22 antagonist, the mechanisms of innate host defense against invading pathogens were analyzed at the infectious focus. Infiltration of effector neutrophils is crucial for the antibacterial host defense during septic peritonitis (5,13,14,30). Neutrophils invading the peritoneal cavity express high levels of Gr-1 (Ly-6B/Ly-6C) and CD11b (Mac-1) (20).…”

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

“…9,10 Recently, TLR9 agonist therapy with CpG DNA has been evaluated in neonatal animals with experimental infection with either lethal neurotropic arenavirus 46 or Listeria monocytogenes, 47 resulting in reduced microbial burden and improved survival in both models. The TLR7/8 agonist resiquimod has not been evaluated in any sepsis model, and no TLR agonist has been previously evaluated in vivo in neonatal mice with polymicrobial sepsis.…”

“…7,8 Stimulating the innate immune system with Toll-like receptor (TLR) agonists improves survival in adult animal models of sepsis. 9,10 Similarly, absence of the adaptive immune system 11 or an inability of B cells to produce antibodies 12 predisposes adult mice to a poor outcome in sepsis. Correction of adaptive immune dysfunction by prevention of lymphocyte apoptosis or treatment with agonistic glucocorticoid-induced tumor necrosis factor (TNF) receptor antibody (anti-GITR) to stimulate effector T-cell function, improves survival in animal models of adult sepsis.…”

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

“…Tolerance to the Gram-positive bacterial cell wall component, BLP has been shown to be associated with downregulation of the TLR2-mediated signal transduction pathway (7,10,11,21,29) and protection against microbial sepsis-related lethality (7)(8)(9)30). However, it is undetermined whether induction of BLP tolerance, like LPSinduced tolerance, is dependent on ST2.…”