Sex-dependent differences in type I IFN-induced natural killer cell activation.

Natural killer (NK) cells are important antiviral effector cells and also involved in tumor clearance. NK cells express IFNAR, rendering them responsive to Type I IFNs. To evaluate Type I IFN-mediated modulation of NK cell functions, individual Type I IFNs subtypes were assessed for their ability to activate NK cells. Different Type I IFN subtypes displayed a broad range in the capacity to induce and modulate NK cell activation and degranulation, measured by CD69 and CD107a expression in response to leukemia cell line K562. When including biological sex as a variable in the analysis, transwell co-cultures of NK cells with either male- or female-derived PBMCs or pDCs stimulated with the TLR7/8 agonist CL097 showed that NK cells were more activated by CL097-stimulated cells derived from females. These sex-specific differences were linked to higher CL097-induced IFNα production by pDCs derived from females, indicating an extrinsic sex-specific effect of Type I IFNs on NK cell function. Interestingly, in addition to the extrinsic effect, we also observed NK cell-intrinsic sex differences, as female NK cells displayed higher activation levels after IFNα-stimulation and after co-culture with CL097-stimulated pDCs, suggesting higher activation of IFNα-signaling transduction in female NK cells. Taken together, the results from these studies identify both extrinsic and intrinsic sex-specific differences in Type I IFN-dependent NK cell functions, contributing to a better understanding of sex-specific differences in innate immunity.

Osteomodulin Gene Expression Is Associated With Plaque Calcification, Stability, and Fewer Cardiovascular Events in the CPIP Cohort.

BACKGROUND: Stable atherosclerotic plaques are characterized by thick fibrous caps of smooth muscle cells, collagen, and macrocalcifications. Identifying factors of plaque stability is necessary to design drugs to prevent plaque rupture and symptoms. Osteomodulin, originally identified in bones, is expressed by bone synthesizing osteoblasts and involved in mineralization. In the present study, we analyzed osteomodulin expression in human carotid plaques, its link with plaque phenotype, calcification, and future cardiovascular events. METHODS: Osteomodulin gene expression (OMD; n=82) was determined by RNA sequencing and osteomodulin protein levels by immunohistochemistry (n=45) in carotid plaques obtained by endarterectomy from patients with or without cerebrovascular symptoms from the CPIP (Carotid Plaque Imaging Project) cohort, Skåne University Hospital, Sweden. Plaque components were assessed by immunohistochemistry, RNA sequencing, and multiplex analysis. Patients were followed for cardiovascular events or cardiovascular death during a median of 57 or 70 months, respectively, using national registers. RESULTS: OMD levels were increased in plaques from asymptomatic patients compared to symptomatics. High OMD levels were associated with fewer cardiovascular events during follow-up. OMD correlated positively with smooth muscle α-actin (ACTA2; r=0.73, P=10-13) and collagen (COL1A2; r=0.4, P=0.0002), but inversely with CD68 gene expression (r=-0.67, P=10-11), lipids (r=-0.37, P=0.001), intraplaque hemorrhage (r=-0.32, P=0.010), inflammatory cytokine, and matrix metalloproteinase plaque contents. OMD was positively associated with MSX2 (Msh Homeobox 2) (r=0.32, P=0.003), a marker of preosteoblast differentiation, BMP4 (bone morphogenetic protein) (r=0.50, P=0.000002) and BMP6 (r=0.47, P=0.000007), plaque calcification (r=0.35, P=0.016), and was strongly upregulated in osteogenically stimulated smooth muscle cells, which was further increased upon BMP stimulation. Osteomodulin protein was present in calcified regions. Osteomodulin protein levels were associated with plaque calcification (r=0.41, P=0.006) and increased in macrocalcified plaques. CONCLUSIONS: These data show that osteomodulin mRNA and protein levels are associated with plaque calcification in human atherosclerosis. Furthermore, osteomodulin mRNA, but not protein levels, is associated with plaque stability.

Resolution of Inflammation Through the Lipoxin and ALX/FPR2 Receptor Pathway Protects Against Abdominal Aortic Aneurysms.

An abdominal aortic aneurysm (AAA) is a progressive aortic dilation that may lead to rupture, which is usually lethal. This study identifies the state of failure in the resolution of inflammation by means of decreased expression of the pro-resolving receptor A lipoxin/formyl peptide receptor 2 (ALX/FPR2) in the adventitia of human AAA lesions. Mimicking this condition by genetic deletion of the murine ALX/FPR2 ortholog in hyperlipidemic mice exacerbated the aortic dilation induced by angiotensin II infusion, associated with decreased vascular collagen and increased inflammation. The authors also identified key roles of lipoxin formation through 12/15-lipoxygenase and neutrophil p38 mitogen-activated protein kinase. In conclusion, this study established pro-resolving signaling by means of the ALX/FPR2 receptor in aneurysms and vascular inflammation.