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.

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.

Type I Interferon Signaling Increases Versican Expression and Synthesis in Lung Stromal Cells During Influenza Infection

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society

2021 Nov 01

Brune, JE;Chang, MY;Altemeier, WA;Frevert, CW;
PMID: 34666527 | DOI: 10.1369/00221554211054447

Versican, a chondroitin sulfate proteoglycan, is an essential component of the extracellular matrix (ECM) in inflammatory lung disease. Versican's potential as an immunomodulatory molecule makes it a promising therapeutic target for controlling host immune responses in the lungs. To establish changes to versican expression and accumulation during influenza A viral pneumonia, we document the temporal and spatial changes to versican mRNA and protein in concert with pulmonary inflammatory cell infiltration. These studies were performed in the lungs of wild-type C57BL6/J mice on days 3, 6, 9, and 12 post-infection with influenza A virus using immunohistochemistry, in situ hybridization, and quantitative digital pathology. Using duplex in situ hybridization, we demonstrate that type I interferon signaling contributes significantly to versican expression in lung stromal cells. Our findings show that versican is a type I interferon-stimulated gene in pulmonary fibroblasts and pericytes in the context of viral pneumonia. These data also provide a guide for future studies to determine the role of versican in the pulmonary immune response to influenza infection.

CCL2-CCR2 signaling in the skin drives surfactant-induced irritant contact dermatitis via IL-1β-mediated neutrophil accumulation

The Journal of investigative dermatology

2021 Sep 21

Shibuya, R;Ishida, Y;Hanakawa, S;Kataoka, TR;Takeuchi, Y;Murata, T;Akagi, A;Chow, Z;Kogame, T;Nakamizo, S;Nakajima, S;Egawa, G;Nomura, T;Kambe, N;Kitoh, A;Kabashima, K;
PMID: 34560074 | DOI: 10.1016/j.jid.2021.07.182

Surfactant-induced cumulative irritant contact dermatitis (ICD) is a common and clinically important skin disorder. CCL2 is known to mediate inflammation following tissue damage in various organs. Thus, we investigated whether and how CCL2 contributes to the development of murine cumulative ICD induced by a common surfactant, sodium dodecyl sulfate (SDS). Wild-type mice treated topically with SDS for 6 consecutive days developed skin inflammation that recapitulated the features of human cumulative ICD, including barrier disruption, epidermal thickening, and neutrophil accumulation. CCL2 was upregulated in SDS-treated skin, and local CCL2 blockade attenuated SDS-induced ICD. SDS-induced ICD and neutrophil accumulation were also attenuated in mice deficient in CCR2, the receptor for CCL2. Neutrophil depletion alleviated SDS-induced ICD, suggesting that impaired neutrophil accumulation was responsible for the amelioration of ICD in CCR2-deficient mice. In RNA-seq analyses of SDS-treated skin, the expression levels of Il1b in CCR2-deficient mice were highly downregulated compared with those in wild-type mice. Furthermore, the intradermal administration of IL-1β in the SDS-treated skin of CCR2-deficient mice restored the local accumulation of neutrophils and the development of ICD. Collectively, our results suggest that CCL2-CCR2 signaling in the skin critically promotes the development of SDS-induced ICD by inducing IL-1β expression for neutrophil accumulation.

Cannabinoid receptor 2 deletion influences social memory and synaptic architecture in the hippocampus

Scientific reports

2021 Aug 19

Komorowska-Müller, JA;Ravichandran, KA;Zimmer, A;Schürmann, B;
PMID: 34413398 | DOI: 10.1038/s41598-021-96285-9

Although the cannabinoid receptor 2 (CB2R) is often thought to play a role mainly outside the brain several publications unequivocally showed the presence of CB2R on hippocampal principal neurons. Activation of CB2R produced a long-lasting membrane potential hyperpolarization, altered the input/output function of CA2/3 principal neurons and produced alterations in gamma oscillations. However, other cellular, molecular and behavioral consequences of hippocampal CB2R signaling have not been studied in detail. Here we demonstrate that the deletion of CB2 leads to a highly significant increase in hippocampal synapsin-I expression levels and particle density, as well as increased vesicular GABA transporter (vGAT) levels. This phenotype was restricted to females and not observed in males. Furthermore, we demonstrate an impairment of social memory in CB2 deficient mice. Our results thus demonstrate that the lack of CB2R leads to changes in the hippocampal synaptic landscape and reveals an important sex-specific difference in endocannabinoid signaling. This study supports a significant role of the CB2R in modulation of different types of memory despite its low expression levels in the brain and provides more insight into a sex-specific role of CB2R in synaptic architecture.

ADAMTS18 deficiency leads to preputial gland hypoplasia and fibrosis in male mice

Reproductive biology

2021 Aug 10

Lin, X;Wu, T;Wang, L;Dang, S;Zhang, W;
PMID: 34388417 | DOI: 10.1016/j.repbio.2021.100542

ADAMTSs (A disintegrin and metalloproteinase with thrombospondin motifs) are a family of 19 secreted zinc metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM) during development, morphogenesis, tissue repair, and remodeling. ADAMTS18 is a poorly characterized member of the ADAMTS family. Previously, ADAMTS18 was found to participate in the development of female reproductive tract in mice. However, whether ADAMTS18 also plays a role in the development of male reproductive system remains unclear. In this study, Adamts18 mRNA was found to be highly expressed in the basal cells of the developing preputial gland. Male Adamts18 knockout (Adamts18-/-) mice exhibit abnormal preputial gland morphogenesis, including reduced size and sharp outline. Histological analyses of preputial gland from 2-week-old male Adamts18-/- mice showed significant atrophy of the whole gland. Preputial glands from 7 months and older Adamts18-/- mice appeared macroscopic swelling on their surface. Histologically, preputial gland swelling is characterized by tissue fibrosis and thicker keratinized squamous cell layer. Preputial gland lesions in age-matched male Adamts18+/+ mice were barely detected. ADAMTS18 deficiency does not lead to significant changes in morphogenesis of prostate and testis in male mice. These results indicate that ADAMTS18 is required for normal morphogenesis and homeostasis of the preputial gland in male mice.

Increased Expression of Heparan Sulfate 6-O-Sulfotransferase-2 Promotes Collagen Production in Cardiac Myofibroblasts

BPB Reports

2021 Jun 06

Kasai, K;Horii, Y;Hironaka, T;Mae, K;Ueno, T;Nagasaka, A;Nakaya, M;
| DOI: 10.1248/bpbreports.4.3_85

Fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) proteins. These excessive ECM proteins are produced by myofibroblasts, which are differentiated mainly from resident fibroblasts in response to tissue injury. In addition to the ECM proteins, the amounts of heparan sulfate, one of the sugar chains, and the proteoglycans attached with heparan sulfate chains are reported to be increased in the fibrotic tissues. However, the contribution of heparan sulfate and heparan sulfate proteoglycans to the development of fibrosis remains unclear. In this study, we found that heparan sulfate 6-O-sulfotransferase-2 (Hs6st2), a type of heparan sulfate transferase, is remarkably induced during fibrosis in the heart, liver, and kidney of mice. We also demonstrated that Hs6st2 was specifically expressed in myofibroblasts of mice with cardiac and liver fibrosis. Hs6st2 knockdown in cardiac myofibroblasts reduced the mRNA expression of fibrosis-related factors, such as Collagen1a1. In summary, this study revealed that Hs6st2 is specifically expressed in myofibroblasts in fibrotic tissues, promotes fibrosis, and can be a good target for the treatment for fibrosis.

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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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