Angiotensin II mobilizes spleen monocytes to promote the development of abdominal aortic aneurysm in Apoe-/- mice.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is widespread among elderly people and results in progressive expansion and rupture of the aorta with high mortality. Macrophages, which are the main population observed within the site of aneurysm, are thought to derive from circulating monocytes although no direct evidence has been provided to date. In this study, we were particularly interested in understanding the trafficking behavior of monocyte subsets in AAA and their role in disease pathogenesis. APPROACH AND RESULTS: Using bone marrow transplantation in Apoe(-/-) mice, we showed that circulating monocytes give rise to abdominal aortic macrophages in hypercholesterolemic mice submitted to angiotensin II (AngII). Detailed monitoring of monocyte compartmentalization revealed that lymphocyte antigen 6C(high) and lymphocyte antigen 6C(low) monocytes transiently increase in blood early after AngII infusion and differentially infiltrate the abdominal aorta. The splenic reservoir accounted for the mobilization of the 2 monocyte subsets after 3 days of AngII infusion. Spleen removal or lymphocyte deficiency in Apoe(-/-) Rag2(-/-) mice similarly impaired early monocyte increase in blood in response to AngII and protected against AAA development, independently of blood pressure. Reconstitution of Apoe(-/-) Rag2(-/-) mice with total splenocytes but not with B-cell-depleted splenocytes restored monocyte mobilization in response to AngII and enhanced susceptibility to AAA. CONCLUSIONS: Taken together, the data show that lymphocyte antigen 6C(high) and lymphocyte antigen 6C(low) monocytes are mobilized from the spleen in response to AngII. Intriguingly, the process is dependent on the presence of B cells and significantly contributes to the development of AAA and the occurrence of aortic rupture.

Screening low-frequency SNPS from genome-wide association study reveals a new risk allele for progression to AIDS.

BACKGROUND: Seven genome-wide association studies (GWAS) have been published in AIDS, and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance. METHODS: We reanalyzed the data from 3 previously published GWAS, targeting specifically low-frequency SNPs (minor allele frequency <5%). Two groups composed of 365 slow progressors and 147 rapid progressors from Europe and the United States were compared with a control group of 1394 seronegative individuals using Eigenstrat corrections. RESULTS: Of the 8584 SNPs with minor allele frequency <5% in cases and controls (Bonferroni threshold = 5.8 × 10⁻6), 4 SNPs showed statistical evidence of association with the slow progressor phenotype. The best result was for HCP5 rs2395029 [P = 8.54 × 10⁻¹5, odds ratio (OR) = 3.41] in the HLA locus, in partial linkage disequilibrium with 2 additional chromosome 6 associations in C6orf48 (P = 3.03 × 10⁻¹°, OR = 2.9) and NOTCH4 (9.08 × 10⁻°7, OR = 2.32). The fourth association corresponded to rs2072255 located in RICH2 (P = 3.30 × 10⁻°6, OR = 0.43) in chromosome 17. Using HCP5 rs2395029 as a covariate, the C6orf48 and NOTCH4 signals disappeared, but the RICH2 signal still remained significant. CONCLUSIONS: Besides the already known chromosome 6 associations, the analysis of low-frequency SNPs brought up a new association in the RICH2 gene. Interestingly, RICH2 interacts with BST-2 known to be a major restriction factor for HIV-1 infection. Our study has thus identified a new candidate gene for AIDS molecular etiology and confirms the interest of singling out low-frequency SNPs to exploit GWAS data.