title: A unique hybrid renal mononuclear phagocyte activation phenotype in murine systemic lupus erythematosus nephritis.
abstract: Renal infiltration with mononuclear cells is associated with poor prognosis in systemic lupus erythematosus. A renal macrophage/dendritic cell signature is associated with the onset of nephritis in NZB/W mice, and immune-modulating therapies can reverse this signature and the associated renal damage despite ongoing immune complex deposition. In nephritic NZB/W mice, renal F4/80(hi)/CD11c(int) macrophages are located throughout the interstitium, whereas F4/80(lo)/CD11c(hi) dendritic cells accumulate in perivascular lymphoid aggregates. We show here that F4/80(hi)/CD11c(int) renal macrophages have a Gr1(lo)/Ly6C(lo)/VLA4(lo)/MHCII(hi)/CD43(lo)/CD62L(lo) phenotype different from that described for inflammatory macrophages. At nephritis onset, F4/80(hi)/CD11c(int) cells upregulate cell surface CD11b, acquire cathepsin and matrix metalloproteinase activity, and accumulate large numbers of autophagocytic vacuoles; these changes reverse after the induction of remission. Latex bead labeling of peripheral blood Gr1(lo) monocytes indicates that these are the source of F4/80(hi)/CD11c(int) macrophages. CD11c(hi)/MHCII(lo) dendritic cells are found in the kidneys only after proteinuria onset, turnover rapidly, and disappear rapidly after remission induction. Gene expression profiling of the F4/80(hi)/CD11c(int) population displays increased expression of proinflammatory, regulatory, and tissue repair/degradation-associated genes at nephritis onset that reverses with remission induction. Our findings suggest that mononuclear phagocytes with an aberrant activation profile contribute to tissue damage in lupus nephritis by mediating both local inflammation and excessive tissue remodeling.
authors.affiliation: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Ramalingam
authors.initials: R
authors.lastname: Bethunaickan
authors.forename: Celine C
authors.initials: CC
authors.lastname: Berthier
authors.forename: Meera
authors.initials: M
authors.lastname: Ramanujam
authors.forename: Ranjit
authors.initials: R
authors.lastname: Sahu
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Yezou
authors.initials: Y
authors.lastname: Sun
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Bottinger
authors.forename: Lionel
authors.initials: L
authors.lastname: Ivashkiv
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Anne
authors.initials: A
authors.lastname: Davidson
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D008181:Lupus Nephritis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D008855:Microscopy, Electron, Scanning; D020411:Oligonucleotide Array Sequence Analysis; D010586:Phagocytes / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D000943:Antigens, Differentiation; D007166:Immunosuppressive Agents; C036763:monocyte-macrophage differentiation antigen; D016753:Interleukin-10; D003520:Cyclophosphamide