Prostaglandin E ₂ –EP2–NF-κB signaling in macrophages as a potential therapeutic target for intracranial aneurysms

Abstract

Intracranial aneurysms are common but are generally untreated, and their rupture can lead to subarachnoid hemorrhage. Because of the poor prognosis associated with subarachnoid hemorrhage, preventing the progression of intracranial aneurysms is critically important. Intracranial aneurysms are caused by chronic inflammation of the arterial wall due to macrophage infiltration triggered by monocyte chemoattractant protein-1 (MCP-1), macrophage activation mediated by the transcription factor nuclear factor κB (NF-κB), and inflammatory signaling involving prostaglandin E (PGE) and prostaglandin E receptor subtype 2 (EP2). We correlated EP2 and cyclooxygenase-2 (COX-2) with macrophage infiltration in human intracranial aneurysm lesions. Monitoring the spatiotemporal pattern of NF-κB activation during intracranial aneurysm development in mice showed that NF-κB was first activated in macrophages in the adventitia and in endothelial cells and, subsequently, in the entire arterial wall. Mice with a macrophage-specific deletion of Ptger2 (which encodes EP2) or macrophage-specific expression of an IκBα mutant that restricts NF-κB activation had fewer intracranial aneurysms with reduced macrophage infiltration and NF-κB activation. In cultured cells, EP2 signaling cooperated with tumor necrosis factor-α (TNF-α) to activate NF-κB and synergistically induce the expression of proinflammatory genes, including Ptgs2 (encoding COX-2). EP2 signaling also stabilized Ccl2 (encoding MCP-1) by activating the RNA-stabilizing protein HuR. Rats administered an EP2 antagonist had reduced macrophage infiltration and intracranial aneurysm formation and progression. This signaling pathway in macrophages thus facilitates intracranial aneurysm development by amplifying inflammation in intracranial arteries. These results indicate that EP2 antagonists may therefore be a therapeutic alternative to surgery.

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“…), this PG cascade is considered as a major mediator of acute inflammation. In addition to such a traditional concept, recent experimental findings including ours have suggested the crucial role of PG cascade in formation and exacerbation of chronic inflammation promoting the IA pathogenesis [5,7]. In brief, NF-κB activation, a hallmark of inflammation in IA lesions [8], can be detected in infiltrating macrophages and endothelial cells in IA lesions of mouse model at the early stage and, later on, spreads to entire arterial walls.…”

“…In addition, such a factor may be applicable to develop drugs for many other macrophage-related diseases. As described in greater detail below, we have recently identified Sphingosine-1-phosphate receptor type 1 (S1P 1 ) and PGE receptor subtype 2 (EP2) as a strong therapeutic target [5,6] (Figure 1).…”

Prostaglandin‐cytokine crosstalk in chronic inflammation

“…Aoki et al . identified the PGE 2 ‐EP 2 ‐NF‐κB signalling cascade in macrophages infiltrating the arterial wall as a factor sustaining the pathogenesis of IA and making the inflammation chronic (Aoki et al ., ). They found that PGE 2 activates NF‐κB synergistically with TNF‐α via EP 2 receptors in macrophages in vitro to induce pro‐inflammatory genes including COX‐2 and the macrophage chemokine CCL2 (also called MCP‐1) and that CCL2 mRNA is also stabilized by this pathway.…”

“…They found that PGE 2 activates NF‐κB synergistically with TNF‐α via EP 2 receptors in macrophages in vitro to induce pro‐inflammatory genes including COX‐2 and the macrophage chemokine CCL2 (also called MCP‐1) and that CCL2 mRNA is also stabilized by this pathway. Consistent with these in vitro findings, mice with macrophage‐specific EP 2 receptor deletion or with transgenic expression of an IκB mutant that restricts NF‐κB activation showed reduced IA incidence with fewer infiltrated macrophages (Aoki et al ., ). Similarly, administration of an EP 2 antagonist in a rat model of IA reduced macrophage infiltration and suppressed IA formation and progression (Aoki et al ., , ).…”

Prevention Effect of Antiplatelets on Aneurysm Rupture in a Mouse Intracranial Aneurysm Model

“…Increased expression of inflammatory mediators such as matrix metalloproteases-9, nuclear factor κB (NF-κB), and tumor necrosis factor-α through the stabilization of inhibitor κB have been listed [13-16], and considered the targets for pharmacological stabilization of intracranial aneurysms. Those include non-steroidal anti-inflammatory drugs, statins, angiotensin-converting enzyme-inhibitors, angiotensin II receptor blockers, NF-κB decoy, and inhibitors of protease such as MMP, and tetracyclines [17].…”