Deletion of Prostaglandin E₂Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever

Abstract

Fever is a hallmark of inflammatory and infectious diseases. The febrile response is triggered by prostaglandin E 2 synthesis mediated by induced expression of the enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). The cellular source for pyrogenic PGE 2 remains a subject of debate; several hypotheses have been forwarded, including immune cells in the periphery and in the brain, as well as the brain endothelium. Here we generated mice with selective deletion of COX-2 and mPGES1 in brain endothelial cells. These mice displayed strongly attenuated febrile responses to peripheral immune challenge. In contrast, inflammationinduced hypoactivity was unaffected, demonstrating the physiological selectivity of the response to the targeted gene deletions. These findings demonstrate that PGE 2 synthesis in brain endothelial cells is critical for inflammation-induced fever.

Immune-Induced Fever Is Mediated by IL-6 Receptors on Brain Endothelial Cells Coupled to STAT3-Dependent Induction of Brain Endothelial Prostaglandin Synthesis

“…However, as we previously reported, the recombination in the brain endothelial cells elicited by the Slco1c1 CreER T2 line may not be complete; when the Cox-2 gene was targeted ϳ15% of the Cox-2 protein induction remained (Wilhelms et al, 2014). It is conceivable that re- maining IL-6R␣ expression in endothelial cells accounts for the residual fever (and Cox-2 expression) seen in the present study.…”

“…However, the mechanism by which IL-6 mediates fever is not clear. Whereas studies using genetically modified animals have shown that IL-1 elicits fever by inducing PGE 2 synthesis in brain endothelial cells (Ching et al, 2007;Ridder et al, 2011;Wilhelms et al, 2014), similar functional studies on the role of IL-6 for the febrile response have been lacking. Receptors for IL-6 exist in two forms, a soluble receptor, sIL-6R, and a membrane bound receptor, IL-6R␣.…”

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

“…The critical role of endothelial cells for the PGE2 production that elicits fever has recently also been demonstrated by targeted deletion of COX-2 and mPGES-1 in brain endothelial cells (Wilhelms et al, 2014). Taken together these studies should end a long controversy concerning this issue (Saper et al, 2012).…”

“…Two main opposing views emerged, one supporting the endothelial cells (Cao et al, 1995;Ek et al, 2001;Matsumura et al, 1998;Yamagata et al, 2001) and the other favoring the perivascular macrophages (Breder and Saper, 1996;Elmquist et al, 1997a;Schiltz and Sawchenko, 2002). To address this question, we (paper I) Hamzic et al, 2013b;Matsuwaki et al, 2014;Wilhelms et al, 2014) and other groups (Chakravarty and Herkenham, 2005;Ching et al, 2007;Gosselin and Rivest, 2008;Ridder et al, 2011) have developed complex transgenic mice models that allowed in vivo analysis of one gene in a BBB cell population at a time (reviewed with paper I).…”

“…In this thesis only global transgenic mice were used (Table 1); however several important studies in immune-to-brain signaling have used conditional transgenic mice Ridder et al, 2011;Wilhelms et al, 2014). Chimeric mice were generated to differentiate between hematopoietic and non-hematopoietic production of PGE2.…”