Temporal Gene Expression in the Hippocampus and Peripheral Organs to Endotoxin-Induced Systemic Inflammatory Response in Caspase-1-Deficient Mice

Abstract

Objectives: Caspase-1 (casp1), a key protease involved in the systemic inflammatory response syndrome (SIRS), controls the brain expression of a set of eight genes: Nos2 and Ptgs2 (nitric oxide synthase 2 and prostaglandin-endoperoxide synthase 2, two inducible enzymes), Cxcl1 and Cxcl10 (C-X-C motif chemokine ligand 1 and ligand 10), Tgtp and Gbp2 (T cell-specific GTPase 1 and guanylate-binding protein 2, two GTPases), Adamts1 (a disintegrin-like and metallopeptidase with thrombospondin type 1 motif, 1, a metalloprotease) and Il1rn (interleukin-1 receptor antagonist). Our objective was to ascertain whether casp1 also controlled the peripheral expression of these genes and, if so, to compare their central versus peripheral patterns of gene expression in immune and endocrine tissues during SIRS. Methods: Wild-type (wt) and casp1 knockout (casp1^-/-) mice were injected with either saline or a high dose of endotoxin/lipopolysaccharide (LPS; 800 μg/mice i.p.). Saline-injected mice were immediately euthanized after injection, whereas LPS-injected mice were sacrificed 6 and 12 h after LPS administration. Hippocampal, splenic and adrenal gene expressions were determined by real-time PCR. Results: Overall, casp1^-/- mice showed a lower inflammatory response than wt mice. The expression levels of powerful proinflammatory factors such as Nos2 and Ptgs2 was reduced in casp1^-/- mice. Moreover, a hierarchical clustering analysis aimed at studying patterns of gene coexpression revealed large alterations in the hippocampal pattern of casp1^-/- mice. Surprisingly, the expression of Adamts1 was increased in the hippocampus and adrenals of casp1^-/- mice. Conclusions: The resilience of casp1^-/- mice to SIRS lethality is associated with a lower inflammatory response, loss of hippocampal gene coexpression patterns, and increased hippocampal Adamts1 gene expression. The latter might be beneficial for casp1^-/- mice, since ADAMTS1 is likely to play a role in neuronal plasticity. The mechanisms described here may help the development of either novel biomarkers or therapeutic targets against SIRS/sepsis.