Table 1.
A brief summary of macrophage modulation studies for prevention of intracranial aneurysms (ICAs) formation and rupture.
| Study Type | Model | Intervention | Macrophage markers | Main Findings | References |
|---|---|---|---|---|---|
| Clinical | – | No intervention | CD68+, CD163+, HLA-DR+ | CD68+, CD163+, HLA-DR- macrophages infiltrate ICAs and correlate with GPAf, loss of α-SMA, wall degeneration, rupture | Ollikainen et al. (46) |
| Clinical | – | No intervention | CD68+, CD163+, CD11b+ | CD68+, CD163+, CD11b+ macrophages increased in ruptured than unruptured ICAs | Froesen et al. (29) |
| Clinical | – | No intervention | HLA-DR+ (M1), CD163+ (M2) | M1 macrophages were dominant compared to M2 macrophages in ruptured ICAs | Hasan et al. (45) |
| Clinical | – | ferumoxytol enhanced MRI | CD68+ | Increased macrophage infiltration in ICAs wall assessed by enhanced uptake of ferumoxytol and CD68+ expression | Hasan et al. (45) |
| Clinical | – | Aspirin 81 mg for 3 months, ferumoxytol enhanced MRI | Decreased inflammation in ICAs due to macrophages with daily intake of Aspirin | Hasan et al. (54) | |
| Preclinical | C57BL/6J mice, Elastase & Ang.IIg induced HTNc | Clodronate MCP-1 KOa, MMP-12 KO |
CD68+ | Increased CD68+ macrophage infiltration in ICAs, macrophage depletion and MCP-1 KO reduced ICAs formation | Kanematsu et al. (33) |
| Preclinical | Male Sprague Dawley rats, left internal carotid artery ligation, elastase and high salt diet | Berberine 200mg/kg/d for 35 days | CD68+ | CD68+ macrophages infiltration in ICAs was decreased by berberine through suppressed expression of MMP-9 and secretion of MCP-1, IL-1β, TNF-α, and IL-6 via down regulation of pFAK/Grp78/UPR signaling pathway | Quan et al. (68) |
| Preclinical | C57BL/6J mice, ligation of left CCA and right renal artery, Ang. II, elastase, 8% NaCl, 0.12% β-aminopropionitrile | anti-CXCL1/GRO-α/KC/CINC-1 antibody | F4/80+, iNOS+ (M1), Arg1+ (M2) | M1/M2 ratio increased in ICAs formation over time, CXCL1 blocked of neutrophils shifted the polarization toward M2 macrophages and reduced aneurysm formation | Nowicki et al. (47) |
| Preclinical | Deoxycorticosterone acetate-salt HTN, elastase | Pioglitazone 10 mg/kg/db, GW9662 2 mg/kg/d for 3 weeks, macrophage PPRγ KO, clodronate liposome depletion of macrophages | CD68+, IL-12 p40 (M1), CD206 (M2), CD36 | Pioglitazone reduced the incidence and rupture of ICAs via reduced infiltration of M1 and M1/M2 ratio in cerebral arteries. Pioglitazone effect was lost in macrophage specific PPRγ KO. Pioglitazone also reduced expression of MCP-1, IL-1 and IL-6. | Shimada et al. (48) |
| Preclinical | Male Sprague Dawley rats, left renal and common carotid arteries ligation, 8% sodium chloride and 0.12% 3‐aminopropionitrile, | Anagliptin 300 mg/kg | Iba-1+, MCP-1+ | Anagliptin prevented the growth of ICAs, inhibited the infiltration and activation of macrophages through reduced MCP-1 expression and suppressed p65 phosphorylation through ERK5 activation. | Ikedo et al. (56) |
| Preclinical | Female Sprague-Dawley rats, Ligation of right common carotid artery and renal artery, 1% saline administration and bilateral oophorectomy | Eplerenone30 or 100 mg/kg/d | CD68+, MCP-1+ | Increased infiltration of CD68+ macrophages in ICAs walls with upregulation of MCP-1 and MMP-9, which was prevented by Eplerenone administration associated with reduced incidence of ICAs. | Tada et al. (57) |
| Preclinical | Sprague-Dawley rats, unilateral ligation of common carotid artery along with β-aminopropionitrile | NF-κB p50 KO, NF-κB decoy ODNd 40 μg/60 μl every 2 weeks | CD68+, MCP-1+ | Activated NF-κB (p65) colocalized with CD68+ macrophages in ICAs and also with MCP-1 and VCAM-1. Gene expression of MCP-1, VCAM-1, MMP-2, MMP-9, IL-1β, and iNOS along with reduced infiltration of CD68+ macrophages was observed in NF-κB p50 KO mice associated with decreased incidence of ICAs formation. Macrophage infiltration, expression of downstream genes, and ICAs formation were dramatically inhibited by NF-κB decoy ODN. | Aoki et al. (16) |
| Preclinical | Sprague-Dawley rats, ligation of left common carotid artery and posterior branches of bilateral renal arteries, 8% sodium chloride and 0.12% β-aminopropionitrile | Nifedipine 10mg/kg/d for 2 months i.pe. | CD68+, MCP-1+ | Nifedipine prevented the enlargement and degeneration of the walls of preexisting ICAs. Nifedinpine led to reduced macrophage infiltration, MCP-1, MMP-2 expression and NF-κB DNA binding. | Aoki et al. (60) |
| Preclinical | Sprague-Dawley rats C57BL/6NCrSlc, Ligation of the left common carotid artery and left renal artery along with a salt loading dose (8% 0.12% 3-aminopropionitrile | Macrophage-specific deletion of Ptger2 (which encodes EP2) or macrophage-specific expression of an IκBα mutant that restricts NF-κB activation, EP2 antagonist |
CD68+ | EP2 and COX-2 correlated with ICAs macrophage infiltration. NF-κB activated in macrophages in the adventitia and in endothelial cells and, subsequently, in the entire arterial wall. Upregulation of proinflammatory genes, including Ptgs2 (encoding COX-2). EP2 signaling also stabilized CCL2 (encoding MCP-1). Rats administered an EP2 antagonist had reduced macrophage infiltration and ICAs formation and progression | Aoki et al. (12) |
aKO, Knock out; bd, day; cHTN, Hypertension; dODN, oligodeoxynucleotide; ei.p, intraperitoneally; fGPA, Glycophorin A; gAng. II, Angiotensin II.