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Systemic Lupus Erythematosus Nephritis Phagocyte Activation

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Systemic Lupus Erythematosus Nephritis Phagocyte Activation The Journal of Immunology A Unique Hybrid Renal Mononuclear Phagocyte Activation Phenotype in Murine Systemic Lupus Erythematosus Nephritis Ramalingam Bethunaickan,* Celine C. Berthier,† Meera Ramanujam,* Ranjit Sahu,* Weijia Zhang,‡ Yezou Sun,‡ Erwin P. Bottinger,‡ Lionel Ivashkiv,x Matthias Kretzler,† and Anne Davidson* 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 F4/80hi/ CD11cint macrophages are located throughout the interstitium, whereas F4/80lo/CD11chi dendritic cells accumulate in perivas- cular lymphoid aggregates. We show here that F4/80hi/CD11cint renal macrophages have a Gr1lo/Ly6Clo/VLA4lo/MHCIIhi/CD43lo/ CD62Llo phenotype different from that described for inflammatory macrophages. At nephritis onset, F4/80hi/CD11cint cells up- regulate cell surface CD11b, acquire cathepsin and matrix metalloproteinase activity, and accumulate large numbers of auto- phagocytic vacuoles; these changes reverse after the induction of remission. Latex bead labeling of peripheral blood Gr1lo monocytes indicates that these are the source of F4/80hi/CD11cint macrophages. CD11chi/MHCIIlo dendritic cells are found in the kidneys only after proteinuria onset, turnover rapidly, and disappear rapidly after remission induction. Gene expression profiling of the F4/80hi/CD11cint 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 inflamma- tion and excessive tissue remodeling. The Journal of Immunology, 2011, 186: 4994–5003. enal mononuclear phagocyte infiltration in human sys- immune complexes and mononuclear cell renal infiltration are temic lupus erythematosus (SLE) nephritis is associated required for renal damage to occur (4). R with poor disease outcome (1) and is linked intricately Macrophages have distinct activation patterns and functions with the activation of the endothelium, renal chemokine pro- depending on the stimuli to which they are exposed (5–8). Clas- duction, proteinuria, complement activation, progressive hypoxia, sically activated (M1) macrophages, induced by TNF-a/IFN-g or and hypertension (2, 3). In NZB/W SLE-prone mice both Fc by IFN-b, have enhanced Ag presentation capabilities and secrete receptor-mediated interaction of mononuclear cells with renal reactive oxygen intermediates, NO, chemokines, and cytokines that induce a Th1 response. Alternatively activated (M2) macro- phages, activated by IL-4 and IL-13 or induced in response to helminths, secrete protective cytokines such as IL-10 and IL1-RA. *Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for These cells express the mannose receptor, Arginase 1, and the † Medical Research, Manhasset, NY 11030; Department of Medicine, University of transcription factors YM1 and FIZZ-1 and are also capable of Michigan Medical School, Ann Arbor, MI 48109; ‡Department of Medicine, Mount Sinai Medical Center, New York, NY 10029; and xWeill Cornell Graduate School of tissue repair (9). Other macrophage activation patterns represent Medical Sciences, New York, NY 10021 a mixed phenotype likely resulting from simultaneous exposure Received for publication September 13, 2010. Accepted for publication February 13, to inflammatory and homeostatic/suppressive factors in vivo. Of 2011. relevance to SLE, macrophages exposed to immune complexes This work was supported by the Alliance for Lupus Research (to A.D., E.B., and and TLR agonists are characterized by an IL-10hi/IL-12lo pheno- W.Z.), National Institutes of Health Grants R01 AI059636-01A2 (to A.D. and L.I.) and R01 DK085241-01 (to C.C.B., M.K., E.B., W.Z., and A.D.), the New York SLE type termed M2b (10). These cells have Ag presentation capa- Foundation, and Rheuminations (to R.B.). bilities and may continue to produce inflammatory cytokines, but The data presented in this article have been submitted to the Gene Expression Om- they are not involved in tissue repair. A somewhat different phe- nibus under accession number GSE27045. notype is induced by ITAM cross-linking in vitro (11). These cells Address correspondence and reprint requests to Dr. Anne Davidson, Feinstein In- do not produce inflammatory cytokines but markedly upregulate stitute for Medical Research, 350 Community Drive, Manhasset, NY 11030. E-mail IL-10 and CXCL13, a chemokine that facilitates lymphoid neo- address: [email protected] genesis. The online version of this article contains supplemental material. Normal mouse kidneys have a heterogeneous population of mono- Abbreviations used in this article: GBM, glomerular basement membrane; IRF, IFN hi hi hi regulatory transcription factor; M1, classically activated; M2, alternatively activated; nuclear phagocytes. The dominant F4/80 /CX3CR1 /MHCII / int int MFI, mean fluorescence intensity; MMP, matrix metalloproteinase; SAM, signifi- CD11b /CD11c renal macrophage population forms a network cance analysis of microarrays; SEM, scanning electron microscopy; SLE, systemic throughout the renal interstitium (12, 13). Normal human kid- lupus erythematosus. neys have a similar interstitial network of CD68+ cells (14). In Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 mice, these intrinsic renal cells use dendrites to sample their local www.jimmunol.org/cgi/doi/10.4049/jimmunol.1003010 The Journal of Immunology 4995 environment, and they can present Ag, but they are poor NO pro- Materials and Methods ducers and are only weakly phagocytic. This has suggested that Mice they are more like dendritic cells (12, 13, 15, 16), and their no- NZB/NZW F1 females were purchased from The Jackson Laboratory (Bar menclature is now a subject of some debate (15). A minor population Harbor, ME). Urine was tested weekly for proteinuria by dipstick (Fisher hi hi of mononuclear cells in normal kidneys is CD11b /CD62L / Scientific, Pittsburgh, PA). After fixed proteinuria appeared, a single dose Ly6Chi/Gr1int/CCR2hi/F4/80lo/CD11clo/MHCIIlo/CD86lo; during of cyclophosphamide and six doses of CTLA4 Ig and anti-CD154 Ab were acute renal inflammation or ischemia, this macrophage population administered as described previously (19). Mice were sacrificed 3–4 wk increases markedly and secretes proinflammatory cytokines (17). after entering complete remission (#30 mg/dl proteinuria on at least two hi hi lo hi occasions 7 d apart). Nephritic mice were sacrificed 2–6 wk after pro- Small populations of CD11b /CD11c and CD11b /CD11c re- teinuria onset but before the development of terminal renal failure. Young nal dendritic cells have been described (18) but have not been well NZB/W F1 mice were sacrificed at 8–16 wk of age. Kidneys also were characterized. obtained from 129/SvJ mice in which anti-glomerular basement membrane In this study, we analyzed the characteristics and function of the (GBM) disease was induced 14 d previously exactly as described (21). major renal mononuclear phagocyte populations from young and Flow cytometry and cell sorting nephritic NZB/W mice and from mice in which remission of nephritis was induced with a combination of cyclophosphamide Single-cell suspensions were prepared from perfused kidneys and stained and costimulatory blockade (19). We show that CD11b+/CD11cint/ with Abs to CD11c, CD11b, CD4, CD8, B220, PDCA, VLA4, MHCII, hi hi CD80, CD86, CD43, CD44, CD62L, Gr1, Ly6C (BD Pharmingen), and F4/80 (F4/80 ) cells, which are the dominant mononuclear cells F4/80 (Caltag-Invitrogen, Carlsbad CA), as described previously (20, 22). in normal renal interstitium, acquire an activated phenotype dur- CD11b+/CD11chi and CD11b+/CD11cint/F4/80hi cells were isolated using ing active nephritis that reverses upon remission induction. During a BD FACSAria IIu cell sorter. A dump gate for CD49b, CD4, CD8, CD5, active SLE nephritis, F4/80hi cells are a major renal source of and B220 was used to exclude NK cells and lymphocytes, and DAPI was used to exclude dead cells. Isolated cells were .90% pure. Cytospin several proinflammatory cytokines and chemokines (20), but they preparations of isolated cells were stained with Wright-Giemsa stain. also secrete molecules associated with tissue protection and repair The proteolytic activities of cathepsins (B, L, and S) and matrix met- that in excess may contribute to tissue degradation. In contrast, alloproteinases (MMPs; MMP2, MMP3, MMP9, and MMP13) were CD11b+/CD11chi/F4/80lo (CD11chi) cells, which are rare in nor- measured in vivo using activatable fluorescent sensors ProSense 680 and mal kidneys, appear in large numbers in lymphoid aggregates MMPSense 680 (Visen Medical, Bedford, MA; Ref. 23). A total of 5 nmol of probe in 100 ml sterile PBS was injected i.v. 24 h before sacrifice, and during nephritis (20) and disappear upon remission induction. kidney cells were stained with Abs to CD11b, CD11c, and F4/80 as above. These two major populations of infiltrating mononuclear cells are F4/80hi cells from nephritic and young mice were sorted into ProSensehi topographically and functionally distinct from each other and are and ProSenselo populations and
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