A PPARγ AGONIST ENHANCES BACTERIAL CLEARANCE THROUGH NEUTROPHIL EXTRACELLULAR TRAP FORMATION AND IMPROVES SURVIVAL IN SEPSIS

Abstract

Dysregulation of the inflammatory response against infection contributes to mortality in sepsis. Inflammation provides critical host defense, but it can cause tissue damage, multiple organ failure and death. Because the nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ) exhibits therapeutic potential, we characterized the role of PPARγ in sepsis. We analyzed severity of clinical signs, survival rates, cytokine production, leukocyte influx, and bacterial clearance in a cecal ligation and puncture (CLP) model of sepsis in Swiss mice. The PPARγ agonist rosiglitazone treatment improved clinical status and mortality, while increasing IL-10 production and decreasing TNF-α and IL-6 levels, and peritoneal neutrophil accumulation 24 h after CLP. We noted increased bacterial killing in rosiglitazone treated mice, correlated with increased generation of reactive oxygen species. Polymorphonuclear leukocytes (PMN) incubated with LPS or E. coli and rosiglitazone increased peritoneal neutrophil extracellular trap (NET)-mediated bacterial killing, an effect reversed by the PPARγ antagonist (GW 9662) treatment. Rosiglitazone also enhanced the release of histones by PMN, a surrogate marker of NET formation, effect abolished by GW 9662. Rosiglitazone modulated the inflammatory response and increased bacterial clearance through PPARγ activation and NET formation, combining immunomodulatory and host-dependent anti-bacterial effects and, therefore, warrants further study as a potential therapeutic agent in sepsis.

Peroxisome Proliferator-Activated Receptor γ Is Essential for the Resolution of Staphylococcus aureus Skin Infections

“…Activation of PPARg in myeloid cells generally opposes inflammation by a variety of mechanisms, most notably the transrepression of inflammatory transcription factors such as nuclear factor kB and activator protein 1 (Araú jo et al, 2016;Remels et al, 2009;Ricote et al, 1998 Xavier et al, 2013). One exception was Pseudomonas aeruginosa.…”

Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation

“…Mice subjected to sham surgery were studied in parallel (n = 3 in each group). Clinical illness severity scores (52) were determined at 24 hours. One-way ANOVA with Newman-Keul post hoc testing; **P < 0.01, nNIF vs. nNIF-SCR groups.…”

“…This may be due to differences in pharmacokinetics or half-lives of nNIF and CRISPP under these conditions. We also performed similar experiments using the cecal ligation and puncture (CLP) model of polymicrobial sepsis (51)(52)(53). Mice treated with nNIF had lower clinical illness scores (52) at 24 hours and significantly increased survival at 144 hours after CLP compared with nNIF-SCRtreated animals ( Figure 9, B and C).…”

Consequences of extracellular trap formation in sepsis

“…An interesting approach towards preventing NETosis while preserving neutrophil function is the finding of Van Avondt et al that cross-linking the signal inhibitory receptor on leukocytes-1 (SIRL-1) obviating NET release from opsonized as well as nonopsonized S. aureus [40]. Additionally, indirect targets such as Peroxisome proliferator-activated receptor gamma (PPARγ) and Phospholipase D2 (PLD2) with modulating effects on NETosis have been considered [16,17]. Temporally appropriate inhibition of NET release may be therapeutically more efficient that attempts to neutralize histones, DNA or other NET components after the cat is out of the bag.…”