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Regulation of dendritic cells and macrophages by an anti-apoptotic cell natural Ab that inhibits inflammatory arthritis

ABSTRACT: Although natural antibodies (NAbs) are present from birth, little is known about what drives their selection, and whether they have housekeeping functions. We now show that the prototypic T15-NAb, first identified because of its protective role in infection, is representative of a previously unknown type of NAb response that specifically recognizes and forms complexes with apoptotic cells, and which promotes cell-corpse engulfment by phagocytes. This T15-NAb-mediated process is dependent on the recruitment of C1q and mannose-binding lectin (MBL), which have known immune modulatory activities that also provide “eat me” signals for phagocytic clearance. Further investigation revealed that, the addition of T15-NAb significantly suppressed in vitro macrophage LPS-induced TNF-alpha and IL-6 secretion, as well as in vitro Toll-like receptor (TLR)-induced dendritic cell maturation and secretion of pro-inflammatory cytokines and chemokines. Significantly, high doses of this B-1 cell produced NAb also inhibited in vivo TLR–induced pro-inflammatory responses, and could suppress autoimmune inflammatory arthritis. These studies identify and characterize a previously unknown regulatory circuit by which a NAb product of innate-like B cells aids homeostasis by control of fundamental inflammatory pathways. Keywords: Dendritic cells, Macrophages, Natural Antibodies, Apoptosis, Inflammation, Arthritis

ORGANISM(S): Mus musculus Homo sapiens unidentified

PROVIDER: GSE14969 | GEO | 2009/08/25

SECONDARY ACCESSION(S): PRJNA111863

REPOSITORIES: GEO

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Project description:Although natural antibodies (NAbs) are present from birth, little is known about what drives their selection, and whether they have housekeeping functions. We now show that the prototypic T15-NAb, first identified because of its protective role in infection, is representative of a previously unknown type of NAb response that specifically recognizes and forms complexes with apoptotic cells, and which promotes cell-corpse engulfment by phagocytes. This T15-NAb-mediated process is dependent on the recruitment of C1q and mannose-binding lectin (MBL), which have known immune modulatory activities that also provide âeat meâ signals for phagocytic clearance. Further investigation revealed that, the addition of T15-NAb significantly suppressed in vitro macrophage LPS-induced TNF-alpha and IL-6 secretion, as well as in vitro Toll-like receptor (TLR)-induced dendritic cell maturation and secretion of pro-inflammatory cytokines and chemokines. Significantly, high doses of this B-1 cell produced NAb also inhibited in vivo TLRâinduced pro-inflammatory responses, and could suppress autoimmune inflammatory arthritis. These studies identify and characterize a previously unknown regulatory circuit by which a NAb product of innate-like B cells aids homeostasis by control of fundamental inflammatory pathways. Keywords: Dendritic cells, Macrophages, Natural Antibodies, Apoptosis, Inflammation, Arthritis In the study presented here, a total of 15 custom-spotted protein slides were hybridized with a T15 IgM monoclonal antibody at three different concentrations, an isotype control IgM, 2 slides were hybridized with serum from naÑve mice, 2 slides incubated with serum from mice immunized with apoptotic cells, 2 slides were incubated with serum from mice immunized with saline, 2 slides were incubated with serum from mice injected with T15 IgM monoclonal antibody, 2 slides were incubated with serum from a lupus-prone mouse disease model and a negative control slide with no antibody hybridized

Project description:Natural antibodies, which arise without known immune exposure, have been described that specifically recognize cells dying from apoptosis but their role in innate immunity remains poorly understood. Herein, we show that the immune response to neo-antigenic determinants on apoptotic thymocytes is dominated by antibodies to oxidation-associated antigens, phosphorylcholine (PC), a head group that becomes exposed during programmed-cell death, and malondialdehyde (MDA), a reactive aldehyde degradation product of polyunsaturated lipids produced following exposure to reactive-oxidation species. While natural antibodies to apoptotic cells in naM-CM-/ve adult mice were dominated by PC and MDA specificities, the amounts of these antibodies were substantially boosted by treatment of mice with apoptotic cells. Moreover, the relative amounts of PC and MDA antibodies was affected by VH gene inheritance. Antibody interactions with apoptotic-cells also mediated the recruitment of C1q, which alone can promote apoptotic-cell phagocytosis by immature dendritic cells. Significantly, IgM-antibodies to both PC and MDA were primary factors in determining the efficiency of serum-dependent apoptotic-cell phagocytosis. Hence, we demonstrate a mechanism by which certain natural antibodies that recognize neo-antigens on apoptotic cells, in naM-CM-/ve mice and those induced by immune exposure to apoptotic-cells, can enhance the functional capabilities of immature dendritic cells for phagocytic engulfment of apoptotic cells. Keywords: Natural antibodies, Inflammation, Complement, Apoptosis In the study presented here, a total of 11 custom-spotted protein slides were hybridized with a T15 IgM monoclonal antibody at three different concentrations, an isotype control IgM, 2 slides were hybridized with serum from naM-QM-^Wve mice, 2 slides incubated with serum from mice immunized with apoptotic cells, 2 slides were incubated with serum from mice immunized with saline, and a negative control slide with no antibody hybridized

Project description:Diabetic nephropathy (DN) as a common complication of diabetes is the primary cause of end-stage renal disease. Sodium butyrate (NaB) is a short chain fatty acid in the metabolic products of intestinal bacterium, and its kidney protective effect has been reported in DN. However, its underlying mechanism remains unclear. The aim of the present study was to investigate the effect of NaB on globe transcriptome changes in DN. In our study, eight-week-male db/db mice which were established DN mice were randomly divided into two groups: the DN+NaB group (DN mice treated with NaB, 5g/kg/day) and the DN group (DN mice treated with saline). Also, the normal db/m mice were used as NC group. Further, blood glucose, body weight, urinary microalbumin and urinary creatinine of mice were measured in three groups. Whole-transcriptome analysis was performed by RNA sequencing (RNA-Seq) to evaluate profiling of lncRNAs and messenger RNAs (mRNAs). Bioinformatic analysis was performed to predict the potential NaB-related lncRNAs and genes in DN. The expressions of lncRNAs and mRNAs were tested by quantitative real-time polymerase chain reaction (qRT-PCR) in renal tissues and mesangial cells treated with NaB. The results of the present study demonstrated that NaB ameliorated renal dysfunction in DN mice. Moreover, RNA-Seq results identified that 17 lncRNAs and 180 mRNAs reversely changed in DN+NaB group when compared with those in DN group. Additionally, the integrated co-expression networks of NaB-related lncRNAs revealed these lncRNAs interacted with 155 key mRNAs. The co-expression networks of mRNAs associated to immune response, antigen processing and presentation and acute inflammatory response to antigenic stimulus. The qRT-PCR data showed that eight mRNAs and seven lncRNAs were dysexpressed by NaB in DN mice and mesangial cell under high glucose condition. Furthermore, the co-expression network of inflammation related lncRNAs and mRNAs demonstrated that those 17 reversed lncRNAs and 37 mRNAs also play essential roles in inflammatory response. In summary, the present study suggests that NaB ameliorates diabetes induced renal dysfunction and regulates transcriptome changes in DN. NaB related lncRNA-mRNA may play roles in the protective effect of NaB in DN.

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Regulation of dendritic cells and macrophages by an anti-apoptotic cell natural Ab that inhibits inflammatory arthritis

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