A Novel Subset of Anti-Inflammatory CD138+ Macrophages Is Deficient in Mice with Experimental Lupus

Abstract

Dead cells accumulating in the tissues may contribute to chronic inflammation. We examined the cause of impaired apoptotic cell clearance human and murine lupus. Dead cells accumulated in bone marrow from lupus patients but not from non-autoimmune patients undergoing myeloablation, where they were efficiently removed by macrophages. Impaired apoptotic cell uptake by macrophages also was seen in mice treated i.p. with pristane (develop lupus) but not mineral oil (MO, do not develop lupus). The inflammatory response to both pristane and MO rapidly depleted resident (Tim4+) large peritoneal macrophages (LPM). The peritoneal exudate of pristane-treated mice contained mainly Ly6Chi inflammatory monocytes, whereas in MO-treated mice, it consisted predominantly of a novel subset of highly phagocytic macrophages resembling small peritoneal macrophages (SPM) that expressed CD138+ and the scavenger receptor Marco. Treatment with anti-Marco neutralizing antibodies and the class A scavenger receptor antagonist polyinosinic acid inhibited phagocytosis of apoptotic cells by CD138+ macrophages. CD138+ macrophages expressed IL-10 receptor, CD206, and CCR2 but little TNFα or CX3CR1. They also expressed high levels of activated CREB, a transcription factor implicated in generating alternatively activated macrophages. Similar cells were identified in the spleen and lung of MO-treated mice and also were induced by lipopolysaccharide. We conclude that highly phagocytic, CD138+ SPM-like cells with an anti-inflammatory phenotype may promote the resolution of inflammation in lupus and infectious diseases. These SPM-like cells are not restricted to the peritoneum, and may help clear apoptotic cells from tissues such as the lung, helping to prevent chronic inflammation.

Differential Responsiveness of Monocyte and Macrophage Subsets to Interferon

“…However, in both pristane-treated and mineral oiltreated mice, surface staining for the scavenger receptor CD36, which promotes the phagocytosis of apoptotic cells (32), was considerably higher in nonclassic monocyte/macrophages versus classic monocyte/macrophages ( Figure 1E). A similar staining pattern was observed for Marco, another scavenger receptor involved in the phagocytosis of apoptotic cells (18,33), with increased staining intensity in nonclassic monocyte/macrophages versus classic monocyte/macrophages, and with higher expression in nonclassic monocyte/macrophages from pristane-treated mice compared to mineral oil-treated mice ( Figure 1E).…”

“…Both subsets expressed chemokine receptors involved in monocyte/macrophage migration ( Figure 1C). As expected, classic monocyte/macrophages expressed more CCR2 than nonclassic monocyte/macrophages (18). Pristane treatment increased the expression of CCR5, CX3CR1, and CCR2 in nonclassic monocyte/macrophages and increased CX3CR1 expression in classic monocyte/macrophages, suggesting that it may promote monocyte/macrophage recruitment to the inflamed peritoneum more potently than monocytes.…”

“…In comparison with classic monocyte/macrophages, nonclassic monocyte/macrophages exhibited higher surface expression of the scavenger receptors CD36 and Marco (Figure E). We showed previously that treatment with anti‐Marco neutralizing antibodies or the class A scavenger receptor antagonist poly(I) reduces in vivo phagocytosis of apoptotic cells by ~30% . Like Marco, the class B scavenger receptor CD36 promotes clearance of apoptotic cells .…”

Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus

“…The pathogenesis of pristane-induced chronic inflammation depends on continuous influx of leukocytes including cDCs and lymphocytes to the inflamed peritoneal cavity and peripheral tissues (75,76). The recruitment of immune cells is tightly regulated by the surrounding cytokine milieu (38,39).…”

Regulation of macrophage activation by proteins expressed on apoptotic neutrophils: Subversion towards autoimmunity by proteinase 3

“…Proresolving mediators, such as dexamethasone, resolvin D1 (RvD1), RvE1 and thrombin enhance the generation of Mres by reducing the efferocytic threshold needed for conversion. 23,39,40 Notably, such efferocytosis-driven phenotype changes are not restricted to the peritoneum but also seem to take place in the liver, spleen, gut and lungs 20,22,36,39,[41][42][43] and can limit metabolic disease, local fibrosis and autoimmune disorders, while enhancing tissue repair.…”