NF-κB-Mediated Inflammation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage. Does Autophagy Play a Role?

Abstract

The rupture of saccular intracranial aneurysms (IA) is the commonest cause of non-traumatic subarachnoid hemorrhage (SAH)—the most serious form of stroke with a high mortality rate. Aneurysm walls are usually characterized by an active inflammatory response, and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) has been identified as the main transcription factor regulating the induction of inflammation-related genes in IA lesions. This transcription factor has also been related to IA rupture and resulting SAH. We and others have shown that autophagy interacts with inflammation in many diseases, but there is no information of such interplay in IA. Moreover, NF-κB, which is a pivotal factor controlling inflammation, is regulated by autophagy-related proteins, and autophagy is regulated by NF-κB signaling. It was also shown that autophagy mediates the normal functioning of vessels, so its disturbance can be associated with vessel-related disorders. Early brain injury, delayed brain injury, and associated cerebral vasospasm are among the most serious consequences of IA rupture and are associated with impaired function of the autophagy⁻lysosomal system. Further studies on the role of the interplay between autophagy and NF-κB-mediated inflammation in IA can help to better understand IA pathogenesis and to identify IA patients with an increased SAH risk.

Keywords: NF-κB; autophagy; delayed brain injury; early brain injury; inflammation; intracranial aneurysm; subarachnoid hemorrhage.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Molecular mechanism of intracranial aneurysm (IA) growth and rupture. Neovascularization (dashed thin red lines) of the vasa vasorum (solid thin red lines) in vascular smooth muscle cells (VSMCs) enables macrophages and other inflammatory cells to penetrate the vessel wall through the layer of endothelial cells (ECs) and secrete substances, mostly proteases, thus thinning and weakening the wall. Such structure of the vessel can rupture, resulting in subarachnoid hemorrhage (SAH), but a trigger, mostly unidentified, is needed to initiate this effect.

Figure 2

Mechanism of IA formation, progression, and rupture. Hemodynamic stress in a blood vessel stimulates inflammation in the endothelial cells (ECs), which promotes lamina degradation and evokes changes in vascular smooth muscle cells (VSMCs), including inflammation, neovascularization and matrix remodeling, which together modify the properties of the blood vessel wall. Permanent inflammation leads to the degeneration of VSMCs, resulting in thinning of the VSMC layers, increase in their fragility, and finally in IA rupture. Red dashed lines denote vasa vasorum, black dashed lines: destroyed lamina, red ovals represent blood cells.

Figure 3

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) can be activated in a canonical (left) or non-canonical (right) pathway to stimulate or repress the expression of genes involved in the regulation of cellular response to stress, immune response, and inflammation. Either pathway is initiated by a ligand bound by its receptor. Some autophagy proteins can be related to both pathways, as discussed in Section 4. This figure is a simplified representation only and does not contain many important details. IKB (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor); IKK: IκB kinase; mTOR: mammalian target of rapamycin; NIK: NF-κB-inducing kinase; TNFR: tumor necrosis factor receptor; ROS: reactive oxygen species. Subunits of NF-κB are shaded with the same, light fiolet color. Sharp arrows represent stimulation/induction, while blunt arrows: inhibition/downregulation, dashed oval: the nucleus.

Figure 4

Molecular mechanism of intracranial aneurysm (IA) formation and progression. A wall shear stress can be an initial trigger in IA formation. This stress can result in some fragile sites (Figure 1) to which macrophages can be recruited by MCP-1 (monocyte chemoattractant protein 1), which is expressed after NF-κB activation, resulting also in the expression of other pro-inflammatory proteins, including COX-2 and PGE-2, in endothelial cells (ECs). Macrophages, which adhere to ECs with the involvement of VCAM-1 protein, find their way to the vessel wall through new vasa vasorum, secrete other pro-inflammatory proteins, including TNF-α, IL-1β, and matrix remodeling proteins such as matrix metalloproteinases MMP-2 and MMP-9. NF-κB activation is mediated by IKK (IκB kinase) and NIK (NF-κB-inducing kinase) proteins, whose activity is regulated by autophagy. The concerted action of these proteins can result in a further weakening of the wall structure and, eventually, in its rupture, but the action of some, yet unidentified factors, can be the final trigger of IA rupture. Black and red solid/dashed lines denote normal/disrupted lamina and vasa vasorum, respectively.

Figure 5

The inflammasome and the interplay between autophagy and NF-κB-mediated inflammation. See the text for more details. PYCARD (apoptosis-associated speck-like protein containing a caspase recruitment domain); DAMP: damage-associated molecular pattern; IKK: IκB kinase; IL: interleukin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NIK: NF-κB-inducing kinase; NLRP3: NLR family pyrin domain containing 3; PAMP: pathogen-associated pattern; TLR4: Toll-like receptor 4.

Figure 6

Macroautophagy dependent on mTOR (mammalian target of rapamycin) can be induced by a lack of nutrients, which leads to the activation of the ULK1 complex, containing UKL1/2, FIP200, ATG13, and ATG101, that is inhibited by the mTOR complex in normal conditions. This complex, with the involvement of Beclin 1, supports the formation of an isolation membrane (phagophore), which encircles the cargo, consisting of damaged and no longer needed cellular components, to form an autophagosome, a double-membrane vehicle which encloses the cargo. The process of autophagosome formation is mediated by several proteins, including LC3, and p62 (SQSTM1), which are essential for autophagy, and involves phospholipids, including phosphatidylethanoamine (PE). The autophagosome fuses with the lysosome forming the autolysosome, in which degradation and recycling of the cargo occurs. Sharp arrows denote stimulation/induction, while blunt arrows: inhibition/downregulation; an X mark denotes abolishing of the inhibitory action of mTOR.

Figure 7

Autophagy in cerebral vessel walls. Damage to endothelial cells (ECs), following a shear stress, can result in pro-death autophagy activation, which increases the consequence of the damage because of a proapoptotic effect and other mechanisms. In addition, disturbances in pro-life autophagy may support the premature senescence of vascular smooth muscle cells (VSMCs), leading to their inability to replace damaged cells.

Figure 8

Involvement of autophagy in subarachnoid hemorrhage (SAH) resulted from rupture of an intracranial aneurysm and its consequent brain injury. Impaired pro-life autophagy can lead to the expansion of damage in endothelial cells (ECs) and vascular muscle smooth cells, by supporting the senescence of these cells and an antiapoptotic effect, which can lead to early brain injury (EBI). Pro-death autophagy can lead to cell death and thinning of EC and VSMC layers and thus participate in IA rupture. Cerebral vasospasm can be associated with delayed brain injury (DBI) after SAH, and autophagy can reduce this effect. Red dashed lines: vasa vasorum, black dashed lines: destroyed lamina.