PPAR-γ/IL-10 Axis Inhibits MyD88 Expression and Ameliorates Murine Polymicrobial Sepsis

Abstract

Polymicrobial sepsis induces organ failure and is accompanied by overwhelming inflammatory response and impairment of microbial killing. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) is a nuclear receptor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. The insulin-sensitizing drugs thiazolidinediones (TZDs) are specific PPAR-γ agonists. TZDs exert anti-inflammatory actions in different disease models, including polymicrobial sepsis. The TZD pioglitazone, which is an FDA-approved drug, improves sepsis outcome; however, the molecular programs that mediate the effect of pioglitazone have not been determined. In a murine model of sepsis, we now show that pioglitazone treatment acts to improve microbial clearance and to enhance neutrophil recruitment to the site of infection. We also observed reduced pro-inflammatory cytokine production and high IL-10 levels in pioglitazone-treated mice. These effects were associated with a decrease in STAT-1-dependent expression of myeloid differentiation factor-88 (MyD88) in vivo and in vitro. IL-10R blockage abolished PPAR-γ-mediated inhibition of MyD88 expression. These data demonstrate that the primary mechanism by which pioglitazone protects against polymicrobial sepsis is by impairing MyD88 responses. This appears to represent a novel regulatory program. In this regard, pioglitazone provides advantages as a therapeutic tool, since it improves different aspects of host defense during sepsis, ultimately enhancing survival.

Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma

“…Since 3-oxo-C 12 -HSL can increase cytosolic calcium, it can be hypothesized that 3-oxo-C 12 -HSL may mediate changes in PPAR␥ and PON-2 levels by modulating the activity of key transcriptional factors (16,17,72,73). The induction of NF-B and interleukin-10 may also play a role in the inhibition of PPAR␥, as these are upregulated by 3-oxo-C 12 -HSL (74,75). …”

Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis

“…Yet, it is not known whether adipocytes contribute to the beneficial effects of TZDs through adiponectin secretion. Also, many of the anti-inflammatory actions attributed to TZDs may be due to their effects on leukocytes (12,20,63). Future research will be needed to assess the contribution of adipose tissue to the systemic inflammatory response and distinguish the metabolic influence of adipose tissue on inflammation from its hormonal influence upon systemic inflammatory responses.…”

SOCS1 is a negative regulator of metabolic reprogramming during sepsis

“…Lung sections from septic and non-septic mice treated with iKIR or the scrambled peptide control were prepared as previously described (79), and sections (5 μm) were stained with H&E, as described previously (85). Sections of stained lung were imaged using an Infinity 1 camera (Lumenera) attached to a Nikon Eclipse Ci microscope.…”

“…Peritoneal lavage fluid and blood were collected from septic mice 18 hours after surgery, as previously described (79). Serial dilutions were plated on Mueller-Hinton agar (Difco Laboratories), and plates were incubated for 18 hours at 37°C.…”