Autoimmune comorbidities associated with sarcoidosis: a case-control study in the All of Us research program

Rheumatology Advances in Practice

2023 Apr 12

Murphy, M;Edemobi, P;Leasure, A;Gulati, M;Miller, E;Damsky, W;Cohen, J;
| DOI: 10.1093/rap/rkad030

Objective The degree to which sarcoidosis patients are affected by autoimmune diseases is poorly understood. Prior studies of autoimmune co-morbidities in sarcoidosis have focused on populations outside the USA or have been impeded by small sample sizes and limited scope. This case-control study evaluated the association between sarcoidosis and autoimmune diseases in a large, diverse cohort based in the USA. Methods We used data from the All of Us research programme to conduct a case-control study involving patients ≥18 years old, from 2018 to the present, diagnosed with sarcoidosis. Sarcoidosis cases and age-, sex- and race-matched controls were identified in a 1:4 ratio. Autoimmune co-morbidities were compared between sarcoidosis patients and controls in univariable and multivariable analyses using logistic regression. The degree of association was measured using the odds ratio (OR). Results A total of 1408 sarcoidosis cases and 5632 controls were included in this study. Seven of 24 examined autoimmune diseases were significantly associated with sarcoidosis in our multivariable analysis (P < 0.05). The composite variable of any autoimmune disease was also significantly associated with sarcoidosis (OR = 2.29, P < 0.001). Conclusion We demonstrate an association between sarcoidosis and multiple autoimmune diseases in a large and diverse cohort based in the USA. These results underscore the need for careful screening of sarcoidosis patients for concomitant autoimmune disease.

A Spatial Atlas of Wnt Receptors in Adult Mouse Liver

The American journal of pathology

2023 Feb 10

Gayden, J;Hu, S;Joseph, PN;Delgado, E;Liu, S;Bell, A;Puig, S;Monga, SP;Freyberg, Z;
PMID: 36773785 | DOI: 10.1016/j.ajpath.2023.01.011

Hepatic zonation is critical for most metabolic functions in liver. Wnt signaling plays an important role in establishing and maintaining liver zonation. Yet, the anatomic expression of Wnt signaling components, especially all 10 Frizzled (Fzd) receptors, has not been characterized in adult liver. To address this, we quantitatively mapped the spatial expression of Fzd receptors in adult mouse liver via multiplex fluorescent in situ hybridization. Although all 10 Fzd receptors are expressed within a metabolic unit, Fzd receptors 1, 4, and 6 are the highest expressed. Although most Wnt signaling occurs in zone 3, expression of most Fzd receptors is not zonated. In contrast, Fzd receptor 6 is preferentially expressed in zone 1. We also verified that Wnt2 and Wnt9b expression is highly zonated and primarily found in zone 3. Therefore, our results suggest that zonated Wnt/β-catenin signaling at baseline is mostly due to Wnt2 and Wnt9b rather than zonation of Fzd mRNA expression. Finally, we showed that Fzd receptors and Wnts are not uniformly expressed by all hepatic cell types. Instead, there is broad distribution among both hepatocytes and nonparenchymal cells, including endothelial cells. Overall, our establishment of a definitive mRNA expression atlas, especially of Fzd receptors, opens the door to future functional characterization in healthy and diseased liver states.

Expression Profile of EBV-Derived Micro-RNA in Systemic Chronic Active EBV Disease

Blood

2022 Nov 15

Yoshimori, M;Ohashi, A;Yoshioka, K;Yokota, T;Shimizu, N;Nishio, M;Arai, A;
| DOI: 10.1182/blood-2022-169693

RESULTS: We identified highly abundant miR-BARTs in the 4 cell lines and the EBV-infected T- or NK-cells from 12 sCAEBV patient's PBMCs (age of 17 to 47 y.o). The expression of miR-BHRFs was not detected in these cells. miR-BART7-3p, miR-BART6-3p, and miR-BART5-5p were the top three expressed among the EBV-derived miRNAs. The highest miR-BART expression among all samples was miR-BART7-3p. We also confirmed the expression of miR-BART7-3p and miR-BART5-5p by _in situ_ hybridization in histological specimens of 3 patients which were observable. Two reports have demonstrated deletion in part of BART region in approximately 30% of sCAEBV cases (_Okuno et al, Nature Microbiology, 2018. Wongwiwat et al, J. Virology, 2022)_. In contrast, no deletion was detected in the region encoding miR-BARTs of EBV obtained from 10 sCAEBV patients. Finally, we examined the role of miR-BART7-3p in sCAEBV. Inhibition of miR-BART7-3p by the inhibitor did not show significant effects on cell proliferation in SNT16 and SNK10 cells. However, GO analysis showed upregulation of immune activation-related genes after miR-BART7-3p inhibition. These results suggest that miR-BART7-3p may function as an immunosuppressor in sCAEBV.

Microenvironmental Factors that Shape Bacterial Metabolites in Inflammatory Bowel Disease

Frontiers in cellular and infection microbiology

2022 Jul 15

Lopez, LR;Ahn, JH;Alves, T;Arthur, JC;
PMID: 35959366 | DOI: 10.3389/fcimb.2022.934619

Inflammatory bowel disease (IBD) is a significant global health problem that involves chronic intestinal inflammation and can involve severe comorbidities, including intestinal fibrosis and inflammation-associated colorectal cancer (CRC). Disease-associated alterations to the intestinal microbiota often include fecal enrichment of Enterobacteriaceae, which are strongly implicated in IBD development. This dysbiosis of intestinal flora accompanies changes in microbial metabolites, shaping host:microbe interactions and disease risk. While there have been numerous studies linking specific bacterial taxa with IBD development, our understanding of microbial function in the context of IBD is limited. Several classes of microbial metabolites have been directly implicated in IBD disease progression, including bacterial siderophores and genotoxins. Yet, our microbiota still harbors thousands of uncharacterized microbial products. In-depth discovery and characterization of disease-associated microbial metabolites is necessary to target these products in IBD treatment strategies. Towards improving our understanding of microbiota metabolites in IBD, it is important to recognize how host relevant factors influence microbiota function. For example, changes in host inflammation status, metal availability, interbacterial community structure, and xenobiotics all play an important role in shaping gut microbial ecology. In this minireview, we outline how each of these factors influences gut microbial function, with a specific focus on IBD-associated Enterobacteriaceae metabolites. Importantly, we discuss how altering the intestinal microenvironment could improve the treatment of intestinal inflammation and associated disorders, like intestinal fibrosis and CRC.

Vascular smooth muscle- and myeloid cell-derived integrin α9β1 does not directly mediate the development of atherosclerosis in mice

Atherosclerosis

2022 Nov 01

Jung, IH;Elenbaas, JS;Burks, KH;Amrute, JM;Xiangyu, Z;Alisio, A;Stitziel, NO;
PMID: 36215801 | DOI: 10.1016/j.atherosclerosis.2022.09.015

Sushi, von Willebrand factor type A, EGF pentraxin domain-containing 1 (SVEP1), an extracellular matrix protein, is a human coronary artery disease locus that promotes atherosclerosis. We previously demonstrated that SVEP1 induces vascular smooth muscle cell (VSMC) proliferation and an inflammatory phenotype in the arterial wall to enhance the development of atherosclerotic plaque. The only receptor known to interact with SVEP1 is integrin α9β1, a cell surface receptor that is expressed by VSMCs and myeloid lineage-derived monocytes and macrophages. Our previous in vitro studies suggested that integrin α9β1 was necessary for SVEP1-induced VSMC proliferation and inflammation; however, the underlying mechanisms mediated by integrin α9β1 in these cell types during the development of atherosclerosis remain poorly understood.Here, using cell-specific gene targeting, we investigated the effects of the integrin α9β1 receptor on VSMCs and myeloid cells in mouse models of atherosclerosis. Interestingly, we found that depleting integrin α9β1 in either VSMCs or myeloid cells did not affect the formation or complexity of atherosclerotic plaque in vessels after either 8 or 16 weeks of high fat diet feeding.Our results indicate that integrin α9β1 in these two cell types does not mediate the in vivo effect of SVEP1 in the development of atherosclerosis. Instead, our results suggest either the presence of other potential receptor(s) or alternative integrin α9β1-expressing cell types responsible for SVEP1 induced signaling in the development of atherosclerosis.

Characterization and mu opioid receptor sensitivity of neuropeptide Y interneurons in the mouse nucleus accumbens

Neuropharmacology

2022 Aug 10

Retzlaff, CL;Rothwell, PE;
PMID: 35963449 | DOI: 10.1016/j.neuropharm.2022.109212

Inhibitory interneurons represent less than 5% of neurons within the nucleus accumbens, but are critical for proper microcircuit function within this brain region. In the dorsal striatum, neuropeptide Y is expressed by two interneuron subtypes (low-threshold spiking interneurons and neurogliaform interneurons) that exhibit mu opioid receptor sensitivity in other brain regions. However, few studies have assessed the molecular and physiological properties of neuropeptide Y interneurons within the nucleus accumbens. We used a transgenic reporter mouse to identify and characterize neuropeptide Y interneurons in acute nucleus accumbens brain slices. Nearly all cells exhibited electrophysiological properties of low-threshold spiking interneurons, with almost no neurogliaform interneurons observed among neuropeptide Y interneurons. We corroborated this pattern using fluorescent in situ hybridization, and also identified a high level of mu opioid receptor expression by low-threshold spiking interneurons, which led us to examine the functional consequences of mu opioid receptor activation in these cells using electrophysiology. Mu opioid receptor activation caused a reduction in the rate of spontaneous action potentials in low-threshold spiking interneurons, as well as a decrease in optogenetically-evoked GABA release onto medium spiny neurons. The latter effect was more robust in female versus male mice, and when the postsynaptic medium spiny neuron expressed the Drd1 dopamine receptor. This work is the first to examine the physiological properties of neuropeptide Y interneurons in the nucleus accumbens, and show they may be an important target for mu opioid receptor modulation by endogenous and exogenous opioids.

Steroidogenic factor 1 regulates transcription of the inhibin B co-receptor in pituitary gonadotrope cells

Endocrinology

2022 Aug 12

Lin, YF;Schang, G;Buddle, ERS;Schultz, H;Willis, TL;Ruf-Zamojski, F;Zamojski, M;Mendelev, N;Boehm, U;Sealfon, SC;Andoniadou, CL;Bernard, DJ;
PMID: 35957608 | DOI: 10.1210/endocr/bqac131

The inhibins control reproduction by suppressing follicle-stimulating hormone synthesis in pituitary gonadotrope cells. The newly discovered inhibin B co-receptor, TGFBR3L, is selectively and highly expressed in gonadotropes in both mice and humans. Here, we describe our initial characterization of mechanisms controlling cell-specific Tgfbr3l/TGFBR3L transcription. We identified two steroidogenic factor 1 (SF-1 or NR5A1) cis-elements in the proximal Tgfbr3l promoter in mice. SF-1 induction of murine Tgfbr3l promoter-reporter activity was inhibited by mutations in one or both sites in heterologous cells. In homologous cells, mutation of these cis-elements or depletion of endogenous SF-1 similarly decreased reporter activity. We observed nearly identical results when using a human TGFBR3L promoter-reporter. The Tgfbr3l gene was tightly compacted and Tgfbr3l mRNA expression was essentially absent in gonadotropes of SF-1 (Nr5a1) conditional knockout mice. During murine embryonic development, Tgfbr3l precedes Nr5a1 expression, though the two transcripts are fully co-localized by embryonic day 18.5 and thereafter. Collectively, these data indicate that SF-1 directly regulates Tgfbr3l/TGFBR3L transcription and is required for post-natal expression of the gene in gonadotropes.

Expression Profiles of ASIC1/2 and TRPV1/4 in Common Skin Tumors

International journal of molecular sciences

2021 Jun 02

Ackermann, K;Wallner, S;Brochhausen, C;Schreml, S;
PMID: 34199609 | DOI: 10.3390/ijms22116024

The acid-sensing ion channels ASIC1 and ASIC2, as well as the transient receptor potential vanilloid channels TRPV1 and TRPV4, are proton-gated cation channels that can be activated by low extracellular pH (pHe), which is a hallmark of the tumor microenvironment in solid tumors. However, the role of these channels in the development of skin tumors is still unclear. In this study, we investigated the expression profiles of ASIC1, ASIC2, TRPV1 and TRPV4 in malignant melanoma (MM), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and in nevus cell nevi (NCN). We conducted immunohistochemistry using paraffin-embedded tissue samples from patients and found that most skin tumors express ASIC1/2 and TRPV1/4. Striking results were that BCCs are often negative for ASIC2, while nearly all SCCs express this marker. Epidermal MM sometimes seem to lack ASIC1 in contrast to NCN. Dermal portions of MM show strong expression of TRPV1 more frequently than dermal NCN portions. Some NCN show a decreasing ASIC1/2 expression in deeper dermal tumor tissue, while MM seem to not lose ASIC1/2 in deeper dermal portions. ASIC1, ASIC2, TRPV1 and TRPV4 in skin tumors might be involved in tumor progression, thus being potential diagnostic and therapeutic targets.

Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects

Cell research

2022 Feb 03

Zhang, Q;Ren, Y;Mo, Y;Guo, P;Liao, P;Luo, Y;Mu, J;Chen, Z;Zhang, Y;Li, Y;Yang, L;Liao, D;Fu, J;Shen, J;Huang, W;Xu, X;Guo, Y;Mei, L;Zuo, Y;Liu, J;Yang, H;Jiang, R;
PMID: 35115667 | DOI: 10.1038/s41422-022-00616-y

Both opioids and nonsteroidal anti-inflammatory drugs (NSAIDS) produce deleterious side effects and fail to provide sustained relief in patients with chronic inflammatory pain. Peripheral neuroinflammation (PN) is critical for initiation and development of inflammatory pain. A better understanding of molecular mechanisms underlying PN would facilitate the discovery of new analgesic targets and the development of new therapeutics. Emerging evidence suggests that peripheral sensory neurons are not only responders to painful stimuli, but are also actively engaged in inflammation and immunity, whereas the intrinsic regulatory mechanism is poorly understood. Here we report the expression of proton-selective ion channel Hv1 in peripheral sensory neurons in rodents and humans, which was previously shown as selectively expressed in microglia in mammalian central nervous system. Neuronal Hv1 was up-regulated by PN or depolarizing stimulation, which in turn aggravates inflammation and nociception. Inhibiting neuronal Hv1 genetically or by a newly discovered selective inhibitor YHV98-4 reduced intracellular alkalization and ROS production in inflammatory pain, mitigated the imbalance in downstream SHP-1-pAKT signaling, and also diminished pro-inflammatory chemokine release to alleviate nociception and morphine-induced hyperalgesia and tolerance. Thus, our data reveal neuronal Hv1 as a novel target in analgesia strategy and managing opioids-related side effects.

TGFB1 mRNA expression is associated with poor prognosis and specific features of inflammation in ccRCC

Virchows Archiv : an international journal of pathology

2022 Feb 02

Takahara, T;Tsuyuki, T;Satou, A;Wada, E;Sakurai, K;Ueda, R;Tsuzuki, T;
PMID: 35112134 | DOI: 10.1007/s00428-021-03256-6

To determine whether TGFB1 affects the immune microenvironment of ccRCC, we investigated the association between TGFB1 expression and clinicopathological features. Tissue microarray was generated from 158 total or partial nephrectomy samples and 12 tumor-adjacent normal kidney tissue. TGFB1 expression was assessed by RNA in situ hybridization and quantified using ImageJ software. TGFB1 was significantly upregulated in ccRCC tissue than in normal kidney tissues (P = 1.03 × 10-9). Tumors with a high WHO/ISUP grade had higher TGFB1 expression levels (P = 7.05 × 10-3). Of 139 patients with localized ccRCC and whose follow-up data were available, those in the TGFB1-high group displayed significantly shorter relapse-free survival than those in the TGFB1-low group (P = 0.0251). TGFB1 expression was significantly upregulated in patients who developed distant metastasis after surgery (n = 12) than in patients without metastasis (n = 127; P = 0.00167). TGFB1 expression positively correlated with the number of PD-L1-positive cells in the tumor stroma (P = 0.0206, ρ = 0.163). Furthermore, TGFB1 expression was associated with the formation of tertiary lymphoid structures. TGF-β1 is a prognostic indicator of worse outcome for ccRCC and might be a therapeutic target in advanced ccRCC. Our data provide new insights into the association between tumor biology and tumor microenvironment in ccRCC.

TRPM4 Contributes to Subthreshold Membrane Potential Oscillations in Multiple Mouse Pacemaker Neurons

eNeuro

2021 Nov 17

Li, K;Shi, Y;Gonye, EC;Bayliss, DA;
PMID: 34732535 | DOI: 10.1523/ENEURO.0212-21.2021

Select neuronal populations display steady rhythmic neuronal firing that provides tonic excitation to drive downstream networks and behaviors. In noradrenergic neurons of the locus coeruleus (LC), circadian neurons of the suprachiasmatic nucleus (SCN), and CO2/H+-activated neurons of the brainstem retrotrapezoid nucleus (RTN), large subthreshold membrane potential oscillations contribute to the pacemaker-like action potential discharge. The oscillations and firing in LC and SCN involve contributions from leak sodium (NALCN) and L-type calcium channels while recent work from RTN suggested an additional pivotal role for a secondary calcium-activated and voltage-gated cationic current sensitive to TRPM4 channel blockers. Here, we tested whether TRPM4 contributes to subthreshold oscillations in mouse LC and SCN. By RNAscope in situ hybridization, Trpm4 transcripts were detected in both cell groups. In whole-cell recordings from acute slice preparations, prominent voltage-dependent membrane potential oscillations were revealed in LC and SCN after blocking action potentials. These oscillations were inhibited by two chemically-distinct blockers of TRPM4, 9-phenanthrol (9-pt) and 4-chloro-2-[[2-(2-chlorophenoxy)acetyl]amino]benzoic acid (CBA). Under whole-cell voltage clamp, inward currents evoked by oscillation voltage waveforms were inhibited in LC by blocking L-type calcium channels and TRPM4. These data implicate TRPM4 in the large subthreshold membrane potential oscillations that underlie tonic action potential discharge in LC and SCN, providing a voltage-dependent and calcium-dependent cationic current to augment the depolarizing inward Na+ and Ca2+ currents previously associated with this distinctive electroresponsive property.

Kisspeptins and the Neuroendocrine Control of Reproduction: Recent Progress and New Frontiers in Kisspeptin Research

Frontiers in Neuroendocrinology

2022 Jan 01

Sobrino, V;Soledad, M;Perdices-López, C;Jimenez-Puyer, M;Tena-Sempere, M;
| DOI: 10.1016/j.yfrne.2021.100977

In late 2003, a major breakthrough in our understanding of the mechanisms that govern reproduction occurred with the identification of the reproductive roles of kisspeptins, encoded by the Kiss1 gene, and their receptor, Gpr54 (aka, Kiss1R). The discovery of this unsuspected reproductive facet attracted an extraordinary interest and boosted an intense research activity, in human and model species, that, in a relatively short period, established a series of basic concepts on the physiological roles of kisspeptins. Such fundamental knowledge, gathered in these early years of kisspeptin research, set the scene for the more recent in-depth dissection of the intimacies of the neuronal networks involving Kiss1 neurons, their precise mechanisms of regulation and the molecular underpinnings of the function of kisspeptins as pivotal regulators of all key aspects of reproductive function, from puberty onset to pulsatile gonadotropin secretion and the metabolic control of fertility. While no clear temporal boundaries between these two periods can be defined, in this review we will summarize the most prominent advances in kisspeptin research occurred in the last ten years, as a means to provide an up-dated view of the state of the art and potential paths of future progress in this dynamic, and ever growing domain of Neuroendocrinology.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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