Brain, behavior, and immunity
Frank, MG;Fleshner, M;Maier, SF;
PMID: 37116592 | DOI: 10.1016/j.bbi.2023.04.009
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produces an array of neurologic and neuropsychiatric symptoms in the acute and post-acute phase of infection (PASC; post-acute sequelae of SARS-CoV-2 infection). Neuroinflammatory processes are considered key factors in the etiology of these symptoms. Several mechanisms underpinning the development of inflammatory events in the brain have been proposed including SARS-CoV-2 neurotropism and peripheral inflammatory responses (i.e., cytokine storm) to infection, which might produce neuroinflammation via immune-to-brain signaling pathways. In this review, we explore evidence in support of an alternate mechanism whereby structural proteins (e.g., spike and spike S1 subunit) derived from SARS-CoV-2 virions function as pathogen-associated molecular patterns (PAMPs) to elicit proinflammatory immune responses in the periphery and/or brain via classical Toll-Like Receptor (TLR) inflammatory pathways. We propose that SARS-CoV-2 structural proteins might directly produce inflammatory processes in brain independent of and/or in addition to peripheral proinflammatory effects, which might converge to play a causal role in the development of neurologic/neuropsychiatric symptoms in COVID-19.
Rheumatology Advances in Practice
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.
The American journal of pathology
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.
Journal of clinical pathology
Humphries, MP;Bingham, V;Abdullah Sidi, F;Craig, S;Lara, B;El-Daly, H;O'Doherty, N;Maxwell, P;Lewis, C;McQuaid, S;Lyness, J;James, J;Snead, DRJ;Salto-Tellez, M;
PMID: 36717223 | DOI: 10.1136/jcp-2022-208525
Interrogation of immune response in autopsy material from patients with SARS-CoV-2 is potentially significant. We aim to describe a validated protocol for the exploration of the molecular physiopathology of SARS-CoV-2 pulmonary disease using multiplex immunofluorescence (mIF).The application of validated assays for the detection of SARS-CoV-2 in tissues, originally developed in our laboratory in the context of oncology, was used to map the topography and complexity of the adaptive immune response at protein and mRNA levels.SARS-CoV-2 is detectable in situ by protein or mRNA, with a sensitivity that could be in part related to disease stage. In formalin-fixed, paraffin-embedded pneumonia material, multiplex immunofluorescent panels are robust, reliable and quantifiable and can detect topographic variations in inflammation related to pathological processes.Clinical autopsies have relevance in understanding diseases of unknown/complex pathophysiology. In particular, autopsy materials are suitable for the detection of SARS-CoV-2 and for the topographic description of the complex tissue-based immune response using mIF.
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.
Frontiers in cellular and infection microbiology
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.
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.
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.
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.
International journal of molecular sciences
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.
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.
Virchows Archiv : an international journal of pathology
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.