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Principal Investigator: Lionel B Ivashkiv
Organization: HOSPITAL FOR SPECIAL SURGERY
Fiscal Year: 2024
Award: $379,852
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Activated synovial macrophages (M[phi]s) are major producers of pathogenic cytokines, and play a key role in
RA pathogenesis. The long term goals of this project are to understand mechanisms that regulate the
balance between activating and feedback inhibitory signaling pathways that are activated in human M[phi]s by
inflammatory factors that drive RA synovitis. An associated goal is to use this knowledge to therapeutically
modulate balance and crosstalk between signaling pathways to promote resolution of inflammation.
Important activators of RA synovial M[phi]s include autocrine TNF, immune complexes, T cell factors,
and damage-associated molecular patterns (DAMPs) generated by tissue damage and cell death. DAMPs
that activate Toll-like receptors (TLRs), which are amongst the most potent activators of M[phi]s and
inflammatory genes such as TNF, IL6, and IL1B, have emerged as important drivers of RA synovial M[phi]
activation. RA synovium contains abundant DAMPs including nucleic acids (NAs) derived from dying cells
that activate intracellular RNA and DNA sensors. Interestingly, RA synovium also abundantly expresses
molecules that bind NAs and potentiate activation of endosomal NA-sensing TLRs (eTLRs: TLR3/7/8/9).
Of the eTLRs, TLR7 and TLR8 are highly expressed in RA synovial macrophages, potently drive
inflammatory cytokine production including in RA synovial explants, and have been most closely implicated
in pathogenesis of RA and inflammatory arthritis models. Human TLR8 is selectively expressed in myeloid
cells and potently drives inflammatory cytokine production, but has been relatively understudied as mouse
TLR8 is non-functional; interestingly, BAC-transgenic mice expressing human TLR8 (hTLR8) exhibit
increased arthritis associated with erosive synovitis, high TNF, and macrophage infiltration that models RA.
In the previous project period we focused on regulation of the balance between activating and
feedback inhibitory pathways downstream of TNF and TLR8 in human M[phi]. We found that the balance of
TLR8 signaling was shifted towards superinduction of inflammatory genes including TNF and IL6 by CXCL4,
which is highly expressed in RA synovium. CXCL4 was previously shown to augment eTLR-mediated IFN
and cytokine production in DCs by binding NAs and promoting their delivery to endolysosomal
compartments. We identified novel and complementary mechanisms whereby CXCL4 activated signaling
and chromatin remodeling in human M[phi]s to boost TLR8 responses. Our overarching hypothesis is that
CXCL4 and eTLRs like TLR8 cooperatively activate signaling and epigenetic mechanisms that result in
synergistic inflammatory gene activation, and that these mechanisms are operative in activated RA synovial
M[phi]s. We propose to investigate mechanisms underlying CXCL4-TLR8 synergy and their pathophysiological
implications for inflammatory arthritis. We anticipate our studies will yield insights that can be used to
attenuate pathologic M[phi] super-activation while leaving basal TLR responses intact for host defense.
Terms: <(TNF)-α><AP-1><AP-1 Enhancer-Binding Protein><AP1><AP1 protein><ATF><Ablation><Activator Protein-1><Amphoterin><Amphoterin Gene><Antibody Response><Antigen-Antibody Complex><Apical><Arthritis><Atrophic Arthritis><Attenuated><Autocrine Systems><B blood cells><B cell><B cell differentiation factor><B cell stimulating factor 2><B cells><B-Cell Differentiation Factor><B-Cell Differentiation Factor Gene><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor 2 Gene><B-Cell Stimulatory Factor-2><B-Cells><B-Lymphocytes><B-cell><BAC clone><BACs><BCDF><BSF-2><BSF-2 Gene><BSF2><BSF2 Gene><Bacterial Artificial Chromosomes><Basal Transcription Factor><Basal transcription factor genes><Beta-2 Gene Interferon><Blood monocyte><Body Tissues><CAP-18><CAP18><CAP18 lipopolysaccharide-binding protein><CRAMP protein><CSIF><CSIF-10><Cachectin><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell surface><Cells><Chemotactic Cytokines><Chromatin><Chromosomal Protein, Nonhistone, HMG1><Chromosomal Protein, Nonhistone, HMG1 Gene><Cnlp><Cytokine Signal Transduction><Cytokine Signaling><Cytokine Synthesis Inhibitory Factor><DNA><Dendritic Cells><Deoxyribonucleic Acid><Disease><Disorder><Endocytosis><Endogenous Interferon Beta><Endosomes><Enhancer-Binding Protein AP1><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Equilibrium><Exhibits><Extracellular Matrix Degradation><FLJ11330><FM1 Gene Product><Feedback><Fibroblast Interferon><Gene Activation><Gene Inactivation><Gene Silencing><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Goals><HMG-1><HMG-1 Gene><HMG-1 Protein><HMG1><HMG1 Gene><HMG3><HMG3 Gene><HMGB1><HMGB1 Protein><HMGB1 gene><HPGF><HSF Gene><Heparin-Binding Protein p30><Hepatocyte Stimulatory Factor Gene><Hepatocyte-Stimulating Factor><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High Mobility Group Protein 1 Gene><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene><High-Mobility Group Box 1><High-Mobility Group Box 1 Gene><Homologous Chemotactic Cytokines><Host Defense><Human><Hybridoma Growth Factor><Hybridoma Growth Factor Gene><Hypoxia><Hypoxic><IFN><IFN-Beta><IFN-beta 2><IFN-β><IFNB2><IFNB2 Gene><IFNb><IKK epsilon><IKKepsilon><IL-10><IL-6><IL-6 Gene><IL10><IL10A><IL6><IL6 Protein><IL6 gene><Immune Complex><Immunoglobulin Enhancer-Binding Protein><In Vitro><Individual><Infiltration><Inflammation><Inflammatory><Inflammatory Arthritis><Intercrines><Interferon-beta><Interferon-β><Interferons><Interleukin 10 Precursor><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin-10><Interleukin-6><Interleukin-6 Gene><Intracellular Communication and Signaling><Joints><Knowledge><LEF Transcription Factor><LL37><Link><Lymphoid Enhancer Factor><MGI-2><Macrophage><Macrophage-Derived TNF><Marrow monocyte><Mediating><Membrana Synovialis Capsulae Articularis><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Monocyte-Derived TNF><Murine><Mus><Myeloid Cells><Myeloid Differentiation-Inducing Protein><Mφ><NF-Kb-Activating Kinase Gene><NF-kB><NF-kappa B><NF-kappaB><NFKB><Natural Interferon Beta><Natural human interferon beta><Non-Polyadenylated RNA><Nonhistone Chromosomal Protein HGM1><Nonhistone Chromosomal Protein HGM1 Gene><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Nucleic Acid Binding><Nucleic Acids><Oxygen Deficiency><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pathway interactions><Patients><Pattern><Peptides><Physiologic><Physiological><Plasmacytoma Growth Factor><Play><Production><RNA><RNA Expression><RNA Gene Products><Receptosomes><Regulation><Resolution><Rheumatoid Arthritis><Ribonucleic Acid><SBP-1><SBP-1 Gene><SIS cytokines><STAT3><STAT3 gene><Seminal><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sulfoglucuronyl Carbohydrate Binding Protein><Sulfoglucuronyl Carbohydrate Binding Protein Gene><Synovial Membrane><Synovitis><Synovium><T Cell Factor><T2K><TBK1><TBK1 gene><TCF Transcription Factor><TIL4><TLR protein><TLR2><TLR2 gene><TLR2 receptor><TLR3><TLR3 gene><TLR7><TLR7 gene><TLR8><TLR8 gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Tissues><Toll-Like Receptor 2><Toll-Like Receptor 3><Toll-Like Receptor 7><Toll-Like Receptor 8><Toll-Like Receptor Family Gene><Toll-like receptors><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Transcription><Transcription Factor AP-1><Transcription Factor NF-kB><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Veiled Cells><Work><activating transcription factor><arthritic><attenuate><attenuates><autocrine><balance><balance function><biological signal transduction><cathelicidin antimicrobial peptide><cathelin-like protein><cathelin-related antimicrobial peptide><chemoattractant cytokine><chemokine><chromatin remodeling><cytokine><epigenetically><epigenomics><gene induction><in vivo Model><induction of genes><inflamed joint><inflamed synovial tissue><inflamed synovium><inhibitor><insight><interferon beta 2><joint damage><joint inflammation><joint injury><joint swelling><joint trauma><kappa B Enhancer Binding Protein><monocyte><necrocytosis><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nuclear factor kappa beta><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><resistance to therapy><resistant to therapy><resolutions><response><rheumatic arthritis><selective expression><selectively expressed><sensor><synergism><synovial inflammation><therapeutic resistance><therapeutic target><therapy resistant><trafficking><transcription factor><transcriptional silencing><treatment resistance>