Pivotal Advance: Activation of cell surface Toll-like receptors causes shedding of the hemoglobin scavenger receptor CD163

Weaver, Lehn K.; Hintz-Goldstein, Katharine A.; Pioli, Patricia A.; Wardwell, Kathleen; Qureshi, Nilofer; Vogel, Stefanie N.; Guyre, Paul M.

doi:10.1189/jlb.1205756

Cited by 149 publications

(129 citation statements)

References 54 publications

(57 reference statements)

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…42 When monocytes and macrophages are stimulated by lipopolysaccharide and other toll-like receptor ligands or when exposed to oxidative stress mediators, CD163 is shed from the cell surface, leading to a reduction in Hb:Hp endocytic capacity. 17,43,44 In agreement with these observations, Hb:Hp-stimulated HO-1 and ferroportin expression were both dramatically reduced when the dexamethasone pretreated monocytes were activated by lipopolysaccharide immediately before Hb:Hp exposure.…”

Section: Discussionsupporting

confidence: 74%

Glucocorticoid treatment skews human monocyte differentiation into a hemoglobin-clearance phenotype with enhanced heme-iron recycling and antioxidant capacity

Vallelian

Schaer²,

Kaempfer³

et al. 2010

Blood

View full text Add to dashboard Cite

Glucocorticoids are used extensively to treat autoimmune hemolytic anemias. Some beneficial effects of glucocorticoid pulse therapy have also been reported in sickle cell disease and paroxysmal nocturnal hemoglobinuria. Based on established concepts of hemoglobin (Hb) toxicity and physiologic Hb scavenger systems, we evaluated whether glucocorticoids could support an adaptive response to extracellular Hb independently of their immunosuppressive activities. Using global proteome and transcriptome analysis with mass-spectrometry (isobaric tag for relative and absolute quantitation and liquid chromatography-mass spectrometry) and gene-array experiments, we found that glucocorticoid treatment in vitro and in patients on glucocorticoid-pulse therapy polarized monocytes into a M2/alternatively activated phenotype with high Hb-scavenger receptor (CD163) expression and enhanced Hbclearance and detoxification capability. Monocytes concurrently exposed to the interactive activity of glucocorticoids and extracellular Hb were characterized by high expression of a group of antioxidant enzymes known to be regulated by the conserved oxidative response transcription factor nuclear factor E2-related factor. Further, suppressed transferrin receptor, together with high ferroportin expression, pointed to a shift in iron homeostasis directed toward an increased cellular export of heme-derived iron. Therefore, stimulating Hb-endocytosis by CD163 and enhancing antioxidative homeostasis and iron recycling may be an essential activity of glucocorticoids that helps alleviate the adverse effects of extracellular Hb. (Blood. 2010;116(24):5347-5356) IntroductionGlucocorticoids are used extensively to treat inflammatory and autoimmune diseases. In autoimmune hemolytic anemia, glucocorticoids are thought to attenuate the production of erythrocytedirected autoantibodies while reducing destruction of immunoglobulin-coated red blood cells by macrophages within the reticuloendothelial system. 1 Intriguingly, randomized clinical trials demonstrated that glucocorticoid pulse therapy also has short-term beneficial effects on complications of nonimmune hemolysis such as acute chest syndrome and pain crisis in children with sickle cell disease. 2,3 Likewise, glucocorticoid treatment of paroxysmal nocturnal hemoglobinuria (PNH) has been advocated to attenuate the severity of hemolytic crisis by not yet established mechanisms. 4 Glucocorticoid treatment of PNH and sickle cell complications is controversial due to the high incidence of treatment-associated complications and rebound attacks. [4][5][6] Nevertheless, these studies could suggest that glucocorticoids might enhance the level of protection against extracellular hemoglobin (Hb) exposure that occurs during nonimmune intravascular hemolysis in PNH and sickle cell disease. In addition, in autoimmune hemolytic anemia plasma, haptoglobin (Hp) is usually consumed pointing to the leakage of free Hb into the circulation.Extracellular Hb has been associated with toxic adverse effects. 7 Free radicals and...

show abstract

Section: Discussionsupporting

confidence: 74%

Glucocorticoid treatment skews human monocyte differentiation into a hemoglobin-clearance phenotype with enhanced heme-iron recycling and antioxidant capacity

Vallelian

Schaer²,

Kaempfer³

et al. 2010

Blood

View full text Add to dashboard Cite

show abstract

“…TLR-2 and TLR-4 receptors are more highly expressed on monocytes. Although these receptors utilize common intracellular signaling pathways, they appear to mediate distinct effects in different cell types (47,48).…”

Section: Discussionmentioning

confidence: 99%

A macrophage marker, siglec‐1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type i interferons and toll‐like receptor agonists

York¹,

Nagai²,

Mangini³

et al. 2007

Arthritis & Rheumatism

282

228

View full text Add to dashboard Cite

Objective. Microarray analyses of peripheral blood leukocytes have shown that patients with systemic lupus erythematosus express increased levels of type I interferon (IFN)-regulated genes. In this study we examined gene expression by peripheral blood mononuclear cells (PBMCs) from patients with systemic sclerosis (SSc) to better understand the dysregulation of the immune system in this disease. Methods. PBMC gene expression was analyzed by microarray and confirmed by real-time polymerase chain reaction (PCR). Surface protein expression of

show abstract

“…This similarity of CD163 levels in steatotic and in non-steatotic human liver could be explained by the limited number of liver samples (47). Furthermore, it is known that CD163 is shed in its soluble form by inflammatory stimuli making sCD163 a specific marker of macrophage activation (48). In view of literature evidence and of the data here reported, it would be interesting to analyze the sCD163 levels in NAFLD patients in order to better delineate new possible parameters for classifying the severity and progression of liver damage.…”

Section: Discussionmentioning

confidence: 99%

Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease

et al. 2012

View full text Add to dashboard Cite

Abstract. Concomitantly to the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children. NAFLD encompasses a spectrum of histological damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), with possible progression to cirrhosis. There is growing evidence that the immune system plays a pivotal role in the initiation and progression to NASH but the cellular nature of the hepatic inflammation is still unknown. The present study includes 34 children with biopsy-proven NAFLD. Liver damage was evaluated by the NAFLD activity score (NAS), and the inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3 and CD163 which are markers of leukocytes, T cells and activated Kupffer cells/macrophages, respectively. Our results have shown that CD45 + (P<0.0001) and CD163 + (P<0.0001) cells were markedly increased in children with severe histological activity (NAS≥5) compared to children with lower activity (NAS<5), whereas CD3 + cells were significantly lower (P<0.01) in children with severe histological activity. There was a significant association between the numbers of CD45 + , CD3 + and CD163 + cells, regarding both the portal tract and liver lobule, and the severity of steatosis, ballooning and fibrosis (P<0.01). These data suggest that the severity and composition of the inflammatory infiltrate correlate with steatosis and the severity of disease in children with NAFLD. Moreover, a decrease in CD3 + cells may be involved in the pathogenesis of liver damage. Future studies should evaluate whether it can predict the progression of liver disease independently of established histological scores.

show abstract

Pivotal Advance: Activation of cell surface Toll-like receptors causes shedding of the hemoglobin scavenger receptor CD163

Cited by 149 publications

References 54 publications

Glucocorticoid treatment skews human monocyte differentiation into a hemoglobin-clearance phenotype with enhanced heme-iron recycling and antioxidant capacity

Glucocorticoid treatment skews human monocyte differentiation into a hemoglobin-clearance phenotype with enhanced heme-iron recycling and antioxidant capacity

A macrophage marker, siglec‐1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type i interferons and toll‐like receptor agonists

Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease

Contact Info

Product

Resources

About