Genetic and Epigenetic Regulation of the Innate Immune Response to Gout.

ABSTRACT

Gout is a disease caused by uric acid (UA) accumulation in the joints, causing inflammation. Two UA forms - monosodium urate (MSU) and soluble uric acid (sUA) have been shown to interact physically with inflammasomes, especially with the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3), albeit the role of the immune response to UA is poorly understood, given that asymptomatic hyperuricemia does also exist. Macrophage phagocytosis of UA activate NLRP3, lead to cytokines release, and ultimately, lead to chemoattract neutrophils and lymphocytes to the gout flare joint spot. Genetic variants of inflammasome genes and of genes encoding their molecular partners may influence hyperuricemia and gout susceptibility, while also influencing other comorbidities such as metabolic syndrome and cardiovascular diseases. In this review, we summarize the inflammatory responses in acute and chronic gout, specifically focusing on innate immune cell mechanisms and genetic and epigenetic characteristics of participating molecules. Unprecedently, a novel UA binding protein - the neuronal apoptosis inhibitor protein (NAIP) - is suggested as responsible for the asymptomatic hyperuricemia paradox.Abbreviation ß2-integrins leukocyte-specific adhesion molecules; ABCG2 ATP-binding cassete family/breast cancer-resistant protein; ACR American college of rheumatology; AIM2 absent in melanoma 2, type of pattern recognition receptor; ALPK1 alpha-protein kinase 1; ANGPTL2 angiopoietin-like protein 2; ASC apoptosis-associated speck-like protein; BIR baculovirus inhibitor of apoptosis protein repeat; BIRC1 baculovirus IAP repeat-containing protein 1; BIRC2 baculoviral IAP repeat-containing protein 2; C5a complement anaphylatoxin; cAMP cyclic adenosine monophosphate; CARD caspase activation and recruitment domains; CARD8 caspase recruitment domain-containing protein 8; CASP1 caspase 1; CCL3 chemokine (C-C motif) ligand 3; CD14 cluster of differentiation 14; CD44 cluster of differentiation 44; Cg05102552 DNA-methylation site, usually cytosine followed by guanine nucleotides; contains arbitrary identification code; CIDEC cell death-inducing DNA fragmentation factor-like effector family; CKD chronic kidney disease; CNV copy number variation; CPT1A carnitine palmitoyl transferase - type 1a; CXCL1 chemokine (CXC motif) ligand 1; DAMPs damage associated molecular patterns; DC dendritic cells; DNMT(1) maintenance DNA methyltransferase; eQTL expression quantitative trait loci; ERK1 extracellular signal-regulated kinase 1; ERK2 extracellular signal-regulated kinase 2; EULAR European league against rheumatism; GMCSF granulocyte-macrophage colony-stimulating factor; GWAS global wide association studies; H3K27me3 tri-methylation at the 27th lysine residue of the histone h3 protein; H3K4me1 mono-methylation at the 4th lysine residue of the histone h3 protein; H3K4me3 tri-methylation at the 4th lysine residue of the histone h3 protein; HOTAIR human gene located between hoxc11 and hoxc12 on chromosome 12; IκBα cytoplasmatic protein/Nf-κb transcription inhibitor; IAP inhibitory apoptosis protein; IFNγ interferon gamma; IL-1ß interleukin 1 beta; IL-12 interleukin 12; IL-17 interleukin 17; IL18 interleukin 18; IL1R1 interleukin-1 receptor; IL-1Ra interleukin-1 receptor antagonist; IL-22 interleukin 22; IL-23 interleukin 23; IL23R interleukin 23 receptor; IL-33 interleukin 33; IL-6 interleukin 6; IMP inosine monophosphate; INSIG1 insulin-induced gene 1; JNK1 c-jun n-terminal kinase 1; lncRNA long non-coding ribonucleic acid; LRR leucine-rich repeats; miR mature non-coding microRNAs measuring from 20 to 24 nucleotides, animal origin; miR-1 miR followed by arbitrary identification code; miR-145 miR followed by arbitrary identification code; miR-146a miR followed by arbitrary identification code, "a" stands for mir family; "a" family presents similar mir sequence to "b" family, but different precursors; miR-20b miR followed by arbitrary identification code; "b" stands for mir family; "b" family presents similar mir sequence to "a" family, but different precursors; miR-221 miR - followed by arbitrary identification code; miR-221-5p miR followed by arbitrary identification code; "5p" indicates different mature miRNAs generated from the 5' arm of the pre-miRNA hairpin; miR-223 miR followed by arbitrary identification code; miR-223-3p mir followed by arbitrary identification code; "3p" indicates different mature miRNAs generated from the 3' arm of the pre-miRNA hairpin; miR-22-3p miR followed by arbitrary identification code, "3p" indicates different mature miRNAs generated from the 3' arm of the pre-miRNA hairpin; MLKL mixed lineage kinase domain-like pseudo kinase; MM2P inductor of m2-macrophage polarization; MSU monosodium urate; mTOR mammalian target of rapamycin; MyD88 myeloid differentiation primary response 88; n-3-PUFAs n-3-polyunsaturated fatty-acids; NACHT acronym for NAIP (neuronal apoptosis inhibitor protein), C2TA (MHC class 2 transcription activator), HET-E (incompatibility locus protein from podospora anserina) and TP1 (telomerase-associated protein); NAIP neuronal apoptosis inhibitory protein (human); Naip1 neuronal apoptosis inhibitory protein type 1 (murine); Naip5 neuronal apoptosis inhibitory protein type 5 (murine); Naip6 neuronal apoptosis inhibitory protein type 6 (murine); NBD nucleotide-binding domain; Nek7 smallest NIMA-related kinase; NET neutrophil extracellular traps; Nf-κB nuclear factor kappa-light-chain-enhancer of activated b cells; NFIL3 nuclear-factor, interleukin 3 regulated protein; NIIMA network of immunity in infection, malignancy, and autoimmunity; NLR nod-like receptor; NLRA nod-like receptor NLRA containing acidic domain; NLRB nod-like receptor NLRA containing BIR domain; NLRC nod-like receptor NLRA containing CARD domain; NLRC4 nod-like receptor family CARD domain containing 4; NLRP nod-like receptor NLRA containing PYD domain; NLRP1 nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 1; NLRP12 nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 12; NLRP3 nod-like receptor family pyrin domain containing 3; NOD2 nucleotide-binding oligomerization domain; NRBP1 nuclear receptor-binding protein; Nrf2 nuclear factor erythroid 2-related factor 2; OR odds ratio; P2X group of membrane ion channels activated by the binding of extracellular; P2X7 p2x purinoceptor 7 gene; p38 member of the mitogen-activated protein kinase family; PAMPs pathogen associated molecular patters; PBMC peripheral blood mononuclear cells; PGGT1B geranylgeranyl transferase type-1 subunit beta; PHGDH phosphoglycerate dehydrogenase; PI3-K phospho-inositol; PPARγ peroxisome proliferator-activated receptor gamma; PPARGC1B peroxisome proliferative activated receptor, gamma, coactivator 1 beta; PR3 proteinase 3 antigen; Pro-CASP1 inactive precursor of caspase 1; Pro-IL1ß inactive precursor of interleukin 1 beta; PRR pattern recognition receptors; PYD pyrin domain; RAPTOR regulatory associated protein of mTOR complex 1; RAS renin-angiotensin system; REDD1 regulated in DNA damage and development 1; ROS reactive oxygen species; rs000*G single nuclear polymorphism, "*G" is related to snp where replaced nucleotide is guanine, usually preceded by an id number; SLC2A9 solute carrier family 2, member 9; SLC7A11 solute carrier family 7, member 11; SMA smooth muscular atrophy; Smac second mitochondrial-derived activator of caspases; SNP single nuclear polymorphism; Sp3 specificity protein 3; ST2 serum stimulation-2; STK11 serine/threonine kinase 11; sUA soluble uric acid; Syk spleen tyrosine kinase; TAK1 transforming growth factor beta activated kinase; Th1 type 1 helper T cells; Th17 type 17 helper T cells; Th2 type 2 helper T cells; Th22 type 22 helper T cells; TLR tool-like receptor; TLR2 toll-like receptor 2; TLR4 toll-like receptor 4; TNFα tumor necrosis factor alpha; TNFR1 tumor necrosis factor receptor 1; TNFR2 tumor necrosis factor receptor 2; UA uric acid; UBAP1 ubiquitin associated protein; ULT urate-lowering therapy; URAT1 urate transporter 1; VDAC1 voltage-dependent anion-selective channel 1.