Cardiac fibroblasts contribute to myocardial dysfunction in mice with sepsis: the role of NLRP3 inflammasome activation.

Abstract

Myocardial contractile dysfunction in sepsis is associated with the increased morbidity and mortality. Although the underlying mechanisms of the cardiac depression have not been fully elucidated, an exaggerated inflammatory response is believed to be responsible. Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome is an intracellular platform that is involved in the maturation and release of interleukin (IL)-1β. The aim of the present study is to evaluate whether sepsis activates NLRP3 inflammasome/caspase-1/IL-1β pathway in cardiac fibroblasts (CFs) and whether this cytokine can subsequently impact the function of cardiomyocytes (cardiac fibroblast-myocyte cross-talk). We show that treatment of CFs with lipopolysaccharide (LPS) induces upregulation of NLRP3, activation of caspase-1, as well as the maturation (activation) and release of IL-1β. In addition, the genetic (small interfering ribonucleic acid [siRNA]) and pharmacological (glyburide) inhibition of the NLRP3 inflammasome in CFs can block this signaling pathway. Furthermore, the inhibition of the NLRP3 inflammasome in cardiac fibroblasts ameliorated the ability of LPS-challenged CFs to impact cardiomyocyte function as assessed by intracellular cyclic adenosine monophosphate (cAMP) responses in cardiomyocytes. Salient features of this the NLP3 inflammasome/ caspase-1 pathway were confirmed in in vivo models of endotoxemia/sepsis. We found that inhibition of the NLRP3 inflammasome attenuated myocardial dysfunction in mice with LPS and increased the survival rate in mice with feces-induced peritonitis. Our results indicate that the activation of the NLRP3 inflammasome in cardiac fibroblasts is pivotal in the induction of myocardial dysfunction in sepsis.

• Authors: Wenbo Zhang, Xuemei Xu, Raymond Kao, Tina Mele, Peter Kvietys, Claudio M Martin, Tao Rui
• Journal: PloS one (PLoS One) Vol. 9 Issue 9 Pg. e107639 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25216263 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• IL1B protein, mouse
• Inflammasomes
• Interleukin-1beta
• Lipopolysaccharides
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Caspase 1

Topics

• Animals
• Cardiomyopathies (complications, genetics, pathology)
• Carrier Proteins (biosynthesis, genetics)
• Caspase 1 (metabolism)
• Fibroblasts (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Humans
• Inflammasomes (genetics)
• Interleukin-1beta (metabolism)
• Lipopolysaccharides (toxicity)
• Mice
• Myocardial Contraction (drug effects)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Sepsis (chemically induced, complications, pathology)
• Signal Transduction (drug effects)