Two subsets of circulating Ly6C ^lo 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 Ly6C ^hi monocytes, we found two subsets of circulating Ly6C ^lo monocytes: one CD138 ^- and a novel CD138 ⁺ subset. Nr4a1 -dependent patrolling Ly6C ^lo monocytes maintain vascular integrity after endothelial injury. Circulating Ly6C ^lo CD138 ⁺ monocytes were associated with DAH and were absent in mice without DAH. They also were absent in Nr4a1 -/- mice, whereas Ly6C ^lo CD138 ^- monocytes were unaffected. However, Nr4a1 -/- mice were susceptible to pristane-induced DAH and lung vasculitis, suggesting that disease onset does not require Ly6C ^lo CD138 ^- monocytes. Peritoneal Ly6C ^lo CD138 ⁺ Mϕ were unchanged in Nr4a1 -/- mice, indicating that they are not derived from Ly6C ^lo CD138 ⁺ monocytes. We conclude that pristane-induced lung microvascular lung injury stimulates a wave of Nr4h1 -dependent Ly6C ^lo CD138 ⁺ patrolling monocytes in an ineffectual effort to maintain vascular integrity in the face of ongoing endothelial damage.