title: High mobility group box 1 skews macrophage polarization and negatively influences phagocytosis of apoptotic cells.
abstract: OBJECTIVE
  Decreased phagocytosis of apoptotic cells plays an important role in the pathogenesis of SLE. This can lead to secondary necrosis and release of nuclear proteins, such as high mobility group box 1 (HMGB1). We hypothesized that increased HMGB1 levels, as present in SLE, skew macrophage differentiation towards M1-like phenotypes and thereby diminish uptake of apoptotic cells. The aim of this study was to investigate the effect of HMGB1 on macrophage polarization and on phagocytic capacity of differentiated macrophages.
  
  
  METHODS
  SLE patients with quiescent disease (SLEDAI ⩽4) and healthy controls (HCs) were included. Monocytes and differentiated M1 and M2 macrophages were assessed for expression of M1 and M2 markers and for phagocytic capacity. HMGB1 was added during differentiation and during phagocytosis.
  
  
  RESULTS
  Expression of CD86 (M1) was not different, whereas CD163 (M2) was significantly lower on SLE monocytes. After differentiation, no differences regarding surface receptor expression and phagocytic capacity were observed between M1 and M2 macrophages from SLE patients and HCs. Addition of HMGB1 during M2 differentiation resulted in high IL-6 and TNF-α mRNA expression and reduced phagocytic capacity of apoptotic cells. Furthermore, adding HMGB1 to apoptotic Jurkat cells diminished phagocytosis of these cells.
  
  
  CONCLUSIONS
  Circulating monocytes from SLE patients display an M1-like phenotype compared with HCs, but in vitro differentiation abolishes this difference. HMGB1 skews differentiation of M2-like macrophages towards an M1-like phenotype and, subsequently, reduces phagocytosis of apoptotic cells. These data imply that the phenotype of monocytes or macrophages is determined by their environment, such as the presence of cytokines and HMGB1.
authors.affiliation: Departments of Rheumatology & Clinical Immunology.
authors.forename: Fleur
authors.initials: F
authors.lastname: Schaper
authors.affiliation: Departments of Rheumatology & Clinical Immunology.
authors.forename: Karina
authors.initials: K
authors.lastname: de Leeuw
authors.affiliation: Departments of Rheumatology & Clinical Immunology.
authors.forename: Gerda
authors.initials: G
authors.lastname: Horst
authors.affiliation: Departments of Rheumatology & Clinical Immunology.
authors.forename: Hendrika
authors.initials: H
authors.lastname: Bootsma
authors.affiliation: Laboratory Medicine.
authors.forename: Pieter C
authors.initials: PC
authors.lastname: Limburg
authors.affiliation: Pathology & Medical Biology, University Medical Center Groningen, University of Groningen.
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
authors.affiliation: Department of Internal Medicine and Rheumatology, Martini Hospital, Groningen, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Bijl
authors.affiliation: Departments of Rheumatology & Clinical Immunology johanna.westra@umcg.nl.
authors.forename: Johanna
authors.initials: J
authors.lastname: Westra
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D024243:HMGB1 Protein / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D019169:Jurkat Cells / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; D012333:RNA, Messenger
keywords: SLE; apoptosis; high mobility group box 1; macrophage; monocyte; phagocytosis; polarization