Search results for "orphan receptor"
showing 6 items of 26 documents
A T-bet gradient controls the fate and function of CCR6−RORγt+ innate lymphoid cells
2013
At mucosal surfaces, the immune system should not initiate inflammatory immune responses to the plethora of antigens constantly present in the environment, but should remain poised to unleash a potent assault on intestinal pathogens. The transcriptional programs and regulatory factors required for immune cells to switch from homeostatic (often tissue-protective) function to potent antimicrobial immunity are poorly defined. Mucosal retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt(+)) innate lymphoid cells (ILCs) are emerging as an important innate lymphocyte population required for immunity to intestinal infections. Various subsets of RORγt(+) ILCs have been described but th…
Human Memory Th17 Cell Populations Change Into Anti-inflammatory Cells With Regulatory Capacity Upon Exposure to Active Vitamin D
2019
Autoimmune diseases are characterized by an aberrantly activated immune system, resulting in tissue damage and functional disability in patients. An important therapeutic goal is to restore the deregulated immunological balance between pro- A nd anti-inflammatory T cells. This imbalance is illustrated by elevated levels and activity of memory Th17 cell populations, such as Th17, Th1/Th17, and Th17.1 cells, in various autoimmune diseases. These cells are characterized by the chemokine receptor CCR6, RORC expression and production of IL-17A, IFNγ, and TNFα. Using rheumatoid arthritis (RA) as a model of autoimmune disease, we here demonstrate that pro-inflammatory memory CCR6+ Th cells can swi…
Discovery of Retinoic Acid-Related Orphan Receptor γt Inverse Agonists via Docking and Negative Image-Based Screening
2018
Retinoic acid-related orphan receptor γt (RORγt) has a vital role in the differentiation of T-helper 17 (TH17) cells. Potent and specific RORγt inverse agonists are sought for treating TH17-related diseases such as psoriasis, rheumatoid arthritis, and type 1 diabetes. Here, the aim was to discover novel RORγt ligands using both standard molecular docking and negative image-based screening. Interestingly, both of these in silico techniques put forward mostly the same compounds for experimental testing. In total, 11 of the 34 molecules purchased for testing were verified as RORγt inverse agonists, thus making the effective hit rate 32%. The pIC50 values for the compounds varied from 4.9 (11 μ…
Transcription factors controlling development and function of innate lymphoid cells.
2014
Abstract Innate lymphoid cells (ILCs) are a heterogeneous group of lymphocytes, which play an important role in tissue homeostasis at epithelial surfaces. They are scarce in spleen and lymph nodes, but substantial numbers can be found in the intestinal mucosa even at steady state. There, they represent the first line of defence against invading pathogens and contribute to lymphorganogenesis, tissue repair and, when inappropriately activated, immune pathology. Lineage-specific development, function and maintenance of these cells depend on a restricted set of transcription factors that partially emerged as a result of diversification and selection during vertebrate evolution. The differential…
Effect of SGLT-2 inhibition in abdominal aortic aneurysm development. Role of RORa in adipose tissue inflammation associated to obesity
2021
El aneurisma aórtico abdominal (AAA) se define como una dilatación local de la arteria aorta a nivel abdominal cuya consecuencia más grave es su ruptura si no se detiene su crecimiento y progresión. Los rasgos patológicos del AAA incluyen un estado inflamatorio crónico que afecta a la pared vascular de la aorta, una degradación progresiva de la matriz extracelular y un aumento en la neovascularización. Esta enfermedad presenta una elevada tasa de mortalidad y en la actualidad el único tratamiento efectivo que se conoce es la intervención quirúrgica, pero no está indicada en pacientes asintomáticos o que presentan un aneurisma de reducido tamaño. Por ello, es fundamental encontrar nuevas est…
Sex steroid hormone receptors, their ligands, and nuclear and non-nuclear pathways
2015
The ability of a cell to respond to a particular hormone depends on the presence of specific receptors for those hormones. Once the hormone has bound to its receptor, and following structural and biochemical modifications to the receptor, it separates from cytoplasmic chaperone proteins, thereby exposing the nuclear localization sequences that result in the activation of the receptor and initiation of the biological actions of the hormone on the target cell. In addition, recent work has demonstrated new pathways of steroid signaling through orphan and cell surface receptors that contribute to more rapid, “non-nuclear” or non-transcriptional effects of steroid hormones, often involving G-pro…