BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages

The resistance of synovial sublining macrophages to apoptosis has a crucial role in joint inflammation and destruction in rheumatoid arthritis (RA). However, the underlying mechanism is incompletely understood. Here we report that inactivation of the pro-apoptotic BCL-2 family protein BAD is essential for survival of synovial sublining macrophage in RA. Genetic disruption of Bad leads to more severe joint inflammation and cartilage and bone damage with reduced apoptosis of synovial sublining macrophages in collagen-induced arthritis (CIA) and TNFα transgenic (TNF-Tg) mouse models. Conversely, Bad3SA/3SA mice, in which BAD can no longer be inactivated by phosphorylation, are protected from collagen-induced arthritis. Mechanistically, phosphorylation-mediated inactivation of BAD specifically protects synovial sublining macrophages from apoptosis in highly inflammatory environment of arthritic joints in CIA and TNF-Tg mice, and in patients with RA, thereby contributing to RA pathology. Our findings put forward a model in which inactivation of BAD confers the apoptosis resistance on synovial sublining macrophages, thereby contributing to the development of arthritis, suggesting that BAD may be a potential therapeutic target for RA.

[1]  Friedrich Paulsen,et al.  Locally renewing resident synovial macrophages provide a protective barrier for the joint , 2019, Nature.

[2]  E. Andreakos,et al.  The many facets of macrophages in rheumatoid arthritis. , 2019, Biochemical pharmacology.

[3]  R. Germain,et al.  Resident Macrophages Cloak Tissue Microlesions to Prevent Neutrophil-Driven Inflammatory Damage , 2019, Cell.

[4]  J. Aguillón,et al.  Humanized Mouse Models of Rheumatoid Arthritis for Studies on Immunopathogenesis and Preclinical Testing of Cell-Based Therapies , 2019, Front. Immunol..

[5]  H. Zhang,et al.  The BH3-only protein BAD mediates TNFα cytotoxicity despite concurrent activation of IKK and NF-κB in septic shock , 2018, Cell Research.

[6]  Wei Wei,et al.  Bcl-XL and Mcl-1 upregulation by calreticulin promotes apoptosis resistance of fibroblast-like synoviocytes via activation of PI3K/Akt and STAT3 pathways in rheumatoid arthritis. , 2018, Clinical and experimental rheumatology.

[7]  G. Kollias,et al.  The p55TNFR-IKK2-Ripk3 axis orchestrates arthritis by regulating death and inflammatory pathways in synovial fibroblasts , 2018, Nature Communications.

[8]  N. Danial,et al.  BAD knockout provides metabolic seizure resistance in a genetic model of epilepsy with sudden unexplained death in epilepsy , 2018, Epilepsia.

[9]  G. Haines,et al.  Association of Increased F4/80high Macrophages With Suppression of Serum‐Transfer Arthritis in Mice With Reduced FLIP in Myeloid Cells , 2017, Arthritis & rheumatology.

[10]  B. Ni,et al.  Tumor Necrosis Factor Alpha Promotes Osteoclast Formation Via PI3K/Akt Pathway‐Mediated Blimp1 Expression Upregulation , 2017, Journal of cellular biochemistry.

[11]  Leonie S. Taams,et al.  MicroRNA-155 contributes to enhanced resistance to apoptosis in monocytes from patients with rheumatoid arthritis , 2017, Journal of autoimmunity.

[12]  D. Hwang,et al.  Transcription factor NFAT5 promotes macrophage survival in rheumatoid arthritis , 2017, The Journal of clinical investigation.

[13]  G. Firestein,et al.  Immunopathogenesis of Rheumatoid Arthritis. , 2017, Immunity.

[14]  C. Tsatsanis,et al.  Akt Signaling Pathway in Macrophage Activation and M1/M2 Polarization , 2017, The Journal of Immunology.

[15]  A. Mantovani,et al.  Macrophage heterogeneity in the context of rheumatoid arthritis , 2016, Nature Reviews Rheumatology.

[16]  S. Tas,et al.  Targeting of proangiogenic signalling pathways in chronic inflammation , 2016, Nature Reviews Rheumatology.

[17]  M. Hattori,et al.  CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis , 2015, Nature Communications.

[18]  K. Jang,et al.  Myeloid deletion of SIRT1 suppresses collagen-induced arthritis in mice by modulating dendritic cell maturation , 2016, Experimental & Molecular Medicine.

[19]  L. Garrett-Sinha,et al.  Deletion of IFT20 in early stage T lymphocyte differentiation inhibits the development of collagen-induced arthritis , 2014, Bone Research.

[20]  F. Marincola,et al.  Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells , 2014, Cell Death and Differentiation.

[21]  E. Hwang,et al.  Platelet-derived Growth Factor-C (PDGF-C) Induces Anti-apoptotic Effects on Macrophages through Akt and Bad Phosphorylation* , 2014, The Journal of Biological Chemistry.

[22]  C. King,et al.  IL-21–Producing Th Cells in Immunity and Autoimmunity , 2013, The Journal of Immunology.

[23]  C. Bao,et al.  Deficiency of β-arrestin1 ameliorates collagen-induced arthritis with impaired TH17 cell differentiation , 2013, Proceedings of the National Academy of Sciences.

[24]  P. V. Schouwenburg,et al.  Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis , 2013, Nature Reviews Rheumatology.

[25]  Jiyan Zhang,et al.  Inactivation of BAD by IKK Inhibits TNFα-Induced Apoptosis Independently of NF-κB Activation , 2013, Cell.

[26]  P. Tak,et al.  Intimal lining layer macrophages but not synovial sublining macrophages display an IL-10 polarized-like phenotype in chronic synovitis , 2012, Arthritis Research & Therapy.

[27]  M. Bogyo,et al.  Treatment of arthritis by macrophage depletion and immunomodulation: testing an apoptosis-mediated therapy in a humanized death receptor mouse model. , 2012, Arthritis and rheumatism.

[28]  Georg Schett,et al.  The pathogenesis of rheumatoid arthritis. , 2011, The New England journal of medicine.

[29]  M. Kool,et al.  A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis , 2011, Nature Genetics.

[30]  D. Veale,et al.  Macrophages in Synovial Inflammation , 2011, Front. Immun..

[31]  S. Gay,et al.  MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis , 2011, Proceedings of the National Academy of Sciences.

[32]  Zhinan Yin,et al.  The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice , 2011, Science.

[33]  Hong-shan Wang,et al.  The adaptor protein CIKS/ACT1 is necessary for collagen-induced arthritis, and it contributes to the production of collagen-specific antibody. , 2010, Arthritis and rheumatism.

[34]  K. Toellner,et al.  IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism , 2010, The Journal of experimental medicine.

[35]  R. Hotchkiss,et al.  Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis. , 2010, Arthritis and rheumatism.

[36]  B. Bresnihan,et al.  Synovial Tissue Sublining CD68 Expression Is a Biomarker of Therapeutic Response in Rheumatoid Arthritis Clinical Trials: Consistency Across Centers , 2009, The Journal of Rheumatology.

[37]  G. Ciliberto,et al.  The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells , 2009, The Journal of experimental medicine.

[38]  N. Danial.  BAD: undertaker by night, candyman by day , 2008, Oncogene.

[39]  S. R. Datta,et al.  Dual role of proapoptotic BAD in insulin secretion and beta cell survival , 2008, Nature Medicine.

[40]  A. Finnegan,et al.  Expression of CD80/86 on B Cells Is Essential for Autoreactive T Cell Activation and the Development of Arthritis1 , 2007, The Journal of Immunology.

[41]  J. Hutcheson,et al.  Pro-apoptotic Bid is required for the resolution of the effector phase of inflammatory arthritis , 2007, Arthritis research & therapy.

[42]  A. Koch,et al.  Macrophages and their products in rheumatoid arthritis , 2007, Current opinion in rheumatology.

[43]  Bo Shi,et al.  Regulation of Mcl-1 expression in rheumatoid arthritis synovial macrophages. , 2006, Arthritis and rheumatism.

[44]  J. Hutcheson,et al.  Bim deficiency leads to exacerbation and prolongation of joint inflammation in experimental arthritis. , 2006, Arthritis and rheumatism.

[45]  S. Snapper,et al.  A crucial role for macrophages in the pathology of K/B × N serum‐induced arthritis , 2005, European journal of immunology.

[46]  Shi Wei,et al.  IL-1 mediates TNF-induced osteoclastogenesis. , 2005, The Journal of clinical investigation.

[47]  A. Zwinderman,et al.  Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis , 2004, Annals of the rheumatic diseases.

[48]  Jing Liu,et al.  JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. , 2004, Molecular cell.

[49]  E. Schwarz,et al.  The TNF-α transgenic mouse model of inflammatory arthritis , 2003, Springer Seminars in Immunopathology.

[50]  S. R. Datta,et al.  Bad-deficient mice develop diffuse large B cell lymphoma , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[51]  E. Clark,et al.  Macrophage- and dendritic cell--dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF. , 2003, Blood.

[52]  G. Firestein.  Evolving concepts of rheumatoid arthritis , 2003, Nature.

[53]  S. R. Datta,et al.  Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. , 2002, Developmental cell.

[54]  R. Pope.  Apoptosis as a therapeutic tool in rheumatoid arthritis , 2002, Nature Reviews Immunology.

[55]  V. Taneja,et al.  CD4 and CD8 T Cells in Susceptibility/Protection to Collagen-Induced Arthritis in HLA-DQ8-Transgenic Mice: Implications for Rheumatoid Arthritis1 , 2002, The Journal of Immunology.

[56]  H. Perlman,et al.  Constitutively Activated Akt-1 Is Vital for the Survival of Human Monocyte-Differentiated Macrophages , 2001, The Journal of experimental medicine.

[57]  B. Bresnihan,et al.  The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. , 2000, Arthritis and rheumatism.

[58]  J. Beijnen,et al.  Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis. , 2000, Arthritis and rheumatism.

[59]  I. Wicks,et al.  Collagen‐induced arthritis in C57BL/6 (H‐2b) mice: new insights into an important disease model of rheumatoid arthritis , 2000, European journal of immunology.

[60]  P. Richards,et al.  Liposomal clodronate eliminates synovial macrophages, reduces inflammation and ameliorates joint destruction in antigen-induced arthritis. , 1999, Rheumatology.

[61]  R. Holmdahl,et al.  B cell‐deficient mice do not develop type II collagen‐induced arthritis (CIA) , 1998, Clinical and experimental immunology.

[62]  S. R. Datta,et al.  Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery , 1997, Cell.

[63]  F. Breedveld,et al.  Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. , 1997, Arthritis and rheumatism.

[64]  E. Gravallese,et al.  Nuclear factor-kappa B in rheumatoid synovium. Localization of p50 and p65. , 1995, Arthritis and rheumatism.

[65]  S. Korsmeyer,et al.  Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death , 1995, Cell.

[66]  D. Kioussis,et al.  Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. , 1991, The EMBO journal.

[67]  R. Maini,et al.  Morphometric comparison of synovium from patients with osteoarthritis and rheumatoid arthritis. , 1988, Journal of clinical pathology.

[68]  Samir Guglani.  Death , 1890, The Lancet.

[69]  John D. Isaacs,et al.  Cytokines in rheumatoid arthritis — shaping the immunological landscape , 2016, Nature Reviews Rheumatology.

[70]  Richard O. Williams,et al.  Protocol for the induction of arthritis in C57BL/6 mice , 2008, Nature Protocols.

[71]  T. Myers,et al.  Expression and location of pro-apoptotic Bcl-2 family protein BAD in normal human tissues and tumor cell lines. , 1998, The American journal of pathology.

[72]  R. Pemberton.  Treatment of arthritis. , 1949, Pennsylvania medical journal.