NR4A1-3 nuclear receptor activity and immune cell dysregulation in rheumatic diseases

Abstract

The development and progression of immune-mediated rheumatic disease (IMRD) involves dysfunction of innate and adaptive immune cell populations leading to altered responses including inflammasome activation, dysregulated cytokine networks, increased immune cell numbers and multifaceted cell-cell communication. Several rheumatic diseases are further characterized by the presence of autoantibodies, immune complex mediated complement activation and the deficit of peripheral immune tolerance due to reduced regulatory T-lymphocyte cell function. Ultimately, in rheumatic disease the loss in cellular and tissue homeostasis culminates in the advancement of chronic inflammation. The three members of the NR4A subfamily of nuclear receptors are immediate early genes, and act as potent transcriptional responders to changes in the cellular and tissue microenvironment. Subfamily members are rapidly expressed in diseases characterized by inflammation and function to control the differentiation and activity of innate and adaptive immune cells in a cell-type and cell-context specific manner. Rheumatic disease including rheumatoid-, psoriatic-, osteo-arthritis and systemic sclerosis display altered NR4A1-3 activity in controlling immune cell migration and function, production of paracrine signaling molecules, synovial tissue hyperplasia, and regulating cartilage turn-over in vivo. Additionally, NR4A1-3 activities mediate cytokine, prostanoid and growth factor signaling to control angiogenesis, modulate the regulatory functions of mesenchymal stromal cells, alter the activation status of dendritic cells, influence the generation of peripheral myeloid and T-lymphocyte lineages and promote the maintenance of functional regulatory T-cells. Further reports uncover the potential of moderating NR4A 1-3 receptors as therapeutic targets in altering immune tolerance, pathological angiogenesis and controlling inflammation in several models of disease.

Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production

“…Additionally, the constitutive activation of NLRP3 inflammasomes carrying pathogenic variants dictates a gene expression program that increases inflammatory genes. This includes the upregulation of nuclear receptors 4A1 and 4A2, which although not previously associated with CAPS, control the inflammatory activation of macrophages and have been implicated in rheumatic diseases 56 . CAPS-associated NLRP3 variants also control other genes related to innate immunity (such as lipocalin 2, C-C chemokine receptor type 7, or the zinc finger endoribonuclease Zc3h12a) and IL-17 responses.…”

Cytoadhesion ofPlasmodium falciparum-infected red blood cells changes the expression of cytokine-, histone- and antiviral protein-encoding genes in brain endothelial cells

“…In inflammatory diseases, NR4A family members are rapidly expressed and control the differentiation and activity of innate and adaptive immune cells. In addition, these proteins mediate cytokine signaling to control angiogenesis (for review (Hamers et al, 2013; Murphy and Crean, 2022)). Furthermore, three genes encoding members of matrix metalloproteinases (MMP1, MMP2, MMP3) are specifically up-regulated only in the presence of iRBCs at elevated temperatures.…”

Tetramethylpyrazine and paeoniflorin combination (TMP-PF) alleviates atherosclerosis progress by reducing hyperlipemia and inhibiting plaque angiogenesis via the NR4A1/VEGFR2 pathway

“…VEGFR2 is a key receptor in VEGF-induced angiogenesis and has been associated with plaque instability, and VEGFR2 antagonism could reduce vascular sprouting in aortic rings of mice [36]. NR4A1 is a subfamily of nuclear receptors, which mainly mediate growth factor and cytokine signaling to regulate angiogenesis, change the activation status of dendritic cells, regulate mesenchymal stromal cells functions, promote the maintenance of functional regulatory T-cells, and influence the generation of peripheral myeloid and T-lymphocyte lineages [37]. In chronic inflammatory conditions, NR4A1 has been shown to regulate pathological angiogenesis [38].…”