**10. Role of inflammation resolution in the growth and rupture of intracranial aneurysms**

The role of inflammation in the growth and rupture of intracranial aneurysms (IAs) has been increasingly recognized over the last few decades; however, the specific role of resolution of inflammation in IAs has not yet been considered [76]. Although the pathophysiology of atherosclerosis and the growth and rupture of IAs are distinct, both conditions are mediated by an underlying inflammatory process [77]. The progression of atherosclerotic plaques determines plaque morphology and the risk of rupture. The degree of macrophage infiltration plays a crucial role in the progression of atherosclerotic plaques. Interestingly, IAs have also been recently regarded as a macrophage-mediated inflammatory disease in which prostaglandin E2 and the master transcription factor NF-kB may be crucial drivers of inflammatory signals [78, 79]. It should be remembered that prostaglandin E2 is derived from the long-chain omega-6 FAs ARA and that EPA can inhibit the generation of eicosanoids from ARA and also downregulates the activity of NF-kB [25].

Atherosclerotic plaques readily incorporate omega-3 FAs, and a higher plaque EPA content is associated with a reduced number of foam cells and macrophages, as well as increased plaque stability, as determined by a well-formed fibrous cap [80]. Additionally, signs of defective resolution of inflammation have been identified in atherosclerotic plaques [81]. One major function of SPMs (particularly maresins) is to induce phenotypic conversion of macrophages, which decrease inflammation and promote tissue regeneration [16]. In animal models of atherosclerosis, a traditional Western high-fat diet disrupts the homeostasis of inflammation resolution by nutrigenetic modulation of the 12/15-LOX pathways, thereby inhibiting the generation of protective SPMs [81, 82]. These recent findings in atherosclerosis, particularly the involvement of docosanoids in vascular inflammation, provide biological plausibility that defective resolution of inflammation is implicated in the pathogenesis of IA growth and rupture.

Human beings evolved, and their genetic patterns were established on a diet with an omega-6/omega-3 FAs ratio of 1/1, whereas in current Western diets, this ratio is around 16/1 [83]. Thus, this extreme nutritional imbalance in current Western diets should be seriously considered as a potential aggravating factor for the growth and rupture of IAs [48, 82]. This suggestion may appear somewhat counterintuitive considering the high prevalence of IAs with increased risk of rupture in the Japanese population, which has one of the highest dietary intakes of omega-3 FAs worldwide [48, 84]. However, nutritional deficiency of long-chain omega-3 FAs may not be the only factor associated with defective resolution of inflammation. Inter-individual and ethnic variations in the susceptibility to IA growth and rupture could be related to tissue-specific enzymatic deficiencies in the biosynthetic routes that regulate the resolution of inflammation. However, while defective resolution has already been associated with other chronic

inflammatory diseases, it is not yet known whether enzymatic deficiencies contribute to IA growth and rupture, and this novel hypothesis requires further investigation [85, 86].
