Genetic and Epigenetic Regulation of the Innate Immune Response to Gout

• Published in: Immunological investigations 2023-04, Vol.52 (3), p.364-397
• Main Authors: de Lima, Jordana Dinorá, de Paula, André Guilherme Portela, Yuasa, Bruna Sadae, de Souza Smanioto, Caio Cesar, da Cruz Silva, Maria Clara, dos Santos, Priscila Ianzen, Prado, Karin Braun, Winter Boldt, Angelica Beate, Braga, Tárcio Teodoro
• Format: Article
• Language: English
• Subjects: Animals; Caspase 1 - metabolism; DNA; DNA Copy Number Variations; Epigenesis, Genetic; Gout - genetics; Histones - metabolism; Humans; Hyperuricemia; IL-1β; Immunity, Innate - genetics; inflammation; Interleukin-1beta - metabolism; Interleukin-23; Leucine - metabolism; Leukocytes, Mononuclear - metabolism; Lysine - metabolism; Mammals - metabolism; Mice; MicroRNAs; MSU; NAIP; Neuronal Apoptosis-Inhibitory Protein - metabolism; NF-kappa B - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; Nucleotides - metabolism; Receptors, Interleukin-1 - metabolism; Symptom Flare Up; Transferases - metabolism; Uric Acid
• ISSN: 0882-0139; 1532-4311
• DOI: 10.1080/08820139.2023.2168554

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: β2-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 qua