Two subsets of circulating Ly6Clo monocytes distinguished by CD138 (syndecan-1) expression and Nr4a1 dependence in pristane-treated mice

Chronic peritoneal inflammation following pristane injection induces lupus with diffuse alveolar hemorrhage (DAH) and pulmonary capillaritis in C57BL/6 mice. The pathogenesis involves pristane-induced microvascular lung injury. BALB/c mice are resistant to endothelial injury and DAH. Lung disease in C57BL/6 mice is abolished by depleting monocytes/macrophages. The objective of this study was to define the role of myeloid subsets in DAH. Hemorrhage and vasculitis were abolished in Ccr2-/- mice, indicating involvement of bone marrow-derived monocytes/macrophages. Along with Ly6Chi monocytes, we found two subsets of circulating Ly6Clo monocytes: one CD138- and a novel CD138+ subset. Nr4a1-dependent patrolling Ly6Clo monocytes maintain vascular integrity after endothelial injury. Circulating Ly6CloCD138+ monocytes were associated with DAH and were absent in mice without DAH. They also were absent in Nr4a1-/- mice, whereas Ly6CloCD138- monocytes were unaffected. However, Nr4a1-/- mice were susceptible to pristane-induced DAH and lung vasculitis, suggesting that disease onset does not require Ly6CloCD138- monocytes. Peritoneal Ly6CloCD138+ M? were unchanged in Nr4a1-/- mice, indicating that they are not derived from Ly6CloCD138+ monocytes. We conclude that pristane-induced lung microvascular lung injury stimulates a wave of Nr4h1-dependent Ly6CloCD138+ patrolling monocytes in an ineffectual effort to maintain vascular integrity in the face of ongoing endothelial damage.

Favorable Cardiovascular Health Is Associated With Lower Hepatocyte Growth Factor Levels in the Multi-Ethnic Study of Atherosclerosis

Introduction: Hepatocyte growth factor (HGF) is a cytokine released in response to endothelial injury and a potential biomarker of cardiovascular disease (CVD) risk. We examined the association between cardiovascular health (CVH) and HGF in a multi-ethnic cohort of adults free from CVD at baseline.Methods: This cross-sectional study conducted between 2020 and 2021 used MESA baseline examination data (2000–2002) from 6,490 US adults aged 45–84 years. The independent variable was CVH measured by the CVH score and number of ideal metrics. The score was derived from seven metrics: smoking, body mass index, physical activity, diet, total cholesterol, blood pressure and blood glucose. Each metric was scored 0 points (poor), 1 point (intermediate) and 2 points (ideal). The total CVH score ranged from 0 to 14. An inadequate score was 0–8, average, 9–10 and optimal, 11–14. The dependent variable was logarithmically transformed HGF. We used regression analyses to estimate associations between CVH and HGF adjusting for sociodemographic factors.Results: Participants' mean (SD) age was 62 (10) years. Fifty-three percent were female. A one-unit increment in the CVH score was significantly associated with 3% lower HGF levels. Average and optimal CVH scores were significantly associated with 8% and 12% lower HGF levels, respectively, compared to inadequate scores. Additionally, a greater number of ideal metrics was associated with lower HGF levels.Conclusion: Favorable CVH was significantly associated with lower HGF levels in this ethnically diverse cohort. Interventions aimed at promoting and preserving favorable CVH may reduce the risk of endothelial injury as indicated by lower serum HGF levels.