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Innate Immune System in Cardiovascular Diseases
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Benjamin J. Kopecky, Kory J. Lavine
Stimulation of the sympathetic nervous system triggers the release of adrenaline and noradrenaline, which results in the maturation and emigration of myeloid cells, favors the production of CCR2+ precursors [34, 113, 117], and mobilizes monocytes to the spleen [118]. Classical monocytes are rapidly recruited to the infarct (~50% from a splenic reservoir) via MCP-1 [17, 119, 120]. Splenectomy post-myocardial infarction is protective and limits myocardial inflammation [121]. During this time, there are high levels of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [122] and proteases [123]. Blockade of monocyte recruitment improves outcomes in murine models of myocardial infarction [124, 125]. CCL2 and CCL7 deficiency inhibits monocyte recruitment post-myocardial infarction and attenuates adverse remodeling [119]. Loss of Nr4a1 (responsible for converting classical to non-classical monocytes) increases classical monocyte and pro-inflammatory macrophage abundance and results in worsening heart function [122]. It is believed that CCR2+ macrophages, monocytes, and neutrophils impact collateral damage to the myocardium and accelerate adverse remodeling [110]. While there is a rapid influx of leukocytes, their persistence within the infarct is short lived (average is 20 hours). Most rapidly infiltrating innate immune cells undergo cell death, with a smaller number of cells exiting the heart and accumulating in the liver, lymph nodes, or spleen [116].
Intraepithelial T cells: Specialized T cells at epithelial surfaces
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
The TCR repertoire of CD8αα+TCRαβ+ nIETs contains self-reactive TCRs that have encountered a high-affinity ligand during their thymic agonist selection process. It was shown that precursors to TCRαβ nIETs express high levels of the immediate early gene Nr4a1 (Nur77), reflecting strong TCR activation signals. The thymic agonist selection process is dependent on an intact store-operated calcium entry (SOCE) pathway to sustain intracellular calcium levels required for TCR-induced maturation. In contrast, positive selection of conventional naïve T cells occurs in the absence of SOCE. Accordingly, thymocytes engineered to express TCRs derived from TCRαβ nIETs show signs of strong TCR activation and mature to coreceptor negative double-negative (DN) T cells that exit the thymus and populate the small intestinal epithelium.
Pterostilbene pre-treatment reduces LPS-induced acute lung injury through activating NR4A1
Published in Pharmaceutical Biology, 2022
Ying Li, Shu-Min Wang, Xing Li, Chang-Jun Lv, Ling-Yun Peng, Xiao-Feng Yu, Ying-Jian Song, Cong-Jie Wang
The nuclear receptor subfamily 4 group A member (NR4A) family, which consists of three members, NR4A1, NR4A2, and NR4A3, is associated with various cellular processes, including cellular proliferation, apoptosis, and energy utilization (Herring et al. 2019). Herring et al. (2019) also reported that NR4A1 and NR4A2 inhibited cell proliferation in the liver, while NR4A3 had the opposite effect in controlling the proliferation of hepatocytes and hepatic stellate cells. Banno et al. (2019) reported that NR4A1 played a pivotal role in regulating inflammatory responses through its function in the NF-κB pathway. In particular, NR4A1 could upregulate the expression of p65 downstream genes by weakening the binding ability of p65 and DNA. NR4A1 directly promoted the expression of IκB (Huang et al. 2016) and regulated the activity of the NF-κB pathway through non-protein-protein interactions (Kalogeris et al. 2012). When investigating other inflammation-related diseases, NR4A1 was demonstrated to inhibit the inflammatory response and delay disease progression (Nakazato et al. 2018). Therefore, we put forward a hypothesis that NR4A1 plays an important role in the LPS induced ALI, and the pre-protective effects of PTE might be associated with the NR4A1 expression.
Yiqi Huoxue Tongluo recipe regulates NR4A1 to improve renal mitochondrial function in unilateral ureteral obstruction (UUO) rats
Published in Pharmaceutical Biology, 2022
Zhen He, Mengjuan Zhang, Hepeng Xu, Wenping Zhou, Chang Xu, Zheng Wang, Ming He, Xiangting Wang
The nuclear receptor superfamily includes at least 48 transcription factors that regulate a variety of cellular and metabolic functions in different biological processes (Chawla et al. 2001). The NR4A family is an orphan nuclear receptor and consists of three members: NR4A1 (NUR77), NR4A2 (NURR 1), and NR4A3 (NOR-1) (Nuclear Receptors Nomenclature Committee 1999). For these receptors, the endogenous ligands are not recognized (Kliewer et al. 1999). Therefore, the regulatory activity of the NR4A1 is ligand-independent, and the function of NR4A1 is receptor-dependent for expression and post-translational modifications (Wang et al. 2003). In Nr4a1–/– mice, the severity of tubular atrophy, tubular casts, and interstitial fibrosis were significantly increased, accompanied by massive infiltration of immune cells, mainly macrophages, T cells, and B cells (Zhang et al. 2018). In our study, we found that the expression of NR4A1 in kidney of UUO rats was increased and inhibited by YHTR and eplerenone (Figure 2).
The tumor microenvironment and triple-negative breast cancer aggressiveness: shedding light on mechanisms and targeting
Published in Expert Opinion on Therapeutic Targets, 2022
Natsuki Furukawa, Vered Stearns, Cesar A. Santa-Maria, Aleksander S. Popel
Biglycan (BGN) is a ubiquitously expressed proteoglycan that acts as a structural component of the extracellular matrix. Upon tissue damage, BGN gets cleaved and released from the ECM and initiates innate immunity reactions by acting as damage-associated molecular patterns (DAMPs) [128]. In TNBC, high expression of BGN is specifically seen in CAFs and differentiated perivascular-like (PVL) subpopulations. High expression of BGN associates with lower infiltration of CD8+ T cells and poor prognosis [129]. Knockout of BGN in the E0771 TNBC murine model led to the normalization of vasculature, improved delivery of chemotherapy, and increased infiltration of CD8+ T cells, indicating that BGN deteriorates the TME to an unfavorable environment [130]. CXCL16 is another molecule secreted by CAFs in TNBC. CXCL16 recruits myeloid cells into the TME of TNBC, which secrete immunosuppressive factors such as S100A9. The recruited myeloid cells further activate CAFs and induce expression of CXCL16, which creates a malignant positive feedback loop to form an immunosuppressive TME [131]. siRNA kinome screening identified PIK3Cδ in CAFs as an important factor that induced invasion of TNBC cells when cocultured with CAFs. Treatment of CAFs with the PIK3Cδ inhibitor CAL-101 altered the secretome of CAFs and induced the secretion of placental growth factor (PLGF) and brain-derived neurotrophic factor (BDNF). These proteins promoted the expression of nuclear receptor subfamily 4 group A (NR4A1), which is a tumor suppressor, in TNBC cells to inhibit invasion [132].