Publications by authors named "Richard H Gomer"

114 Publications

Cell dispersal by localized degradation of a chemoattractant.

Proc Natl Acad Sci U S A 2021 Feb;118(6)

Department of Physics, University of California San Diego, La Jolla, CA 92093;

Chemotaxis, the guided motion of cells by chemical gradients, plays a crucial role in many biological processes. In the social amoeba , chemotaxis is critical for the formation of cell aggregates during starvation. The cells in these aggregates generate a pulse of the chemoattractant, cyclic adenosine 3',5'-monophosphate (cAMP), every 6 min to 10 min, resulting in surrounding cells moving toward the aggregate. In addition to periodic pulses of cAMP, the cells also secrete phosphodiesterase (PDE), which degrades cAMP and prevents the accumulation of the chemoattractant. Here we show that small aggregates of can disperse, with cells moving away from instead of toward the aggregate. This surprising behavior often exhibited oscillatory cycles of motion toward and away from the aggregate. Furthermore, the onset of outward cell motion was associated with a doubling of the cAMP signaling period. Computational modeling suggests that this dispersal arises from a competition between secreted cAMP and PDE, creating a cAMP gradient that is directed away from the aggregate, resulting in outward cell motion. The model was able to predict the effect of PDE inhibition as well as global addition of exogenous PDE, and these predictions were subsequently verified in experiments. These results suggest that localized degradation of a chemoattractant is a mechanism for morphogenesis.
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http://dx.doi.org/10.1073/pnas.2008126118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017704PMC
February 2021

Serum Amyloid P inhibits single stranded RNA-induced lung inflammation, lung damage, and cytokine storm in mice.

PLoS One 2021 22;16(1):e0245924. Epub 2021 Jan 22.

Department of Biology, Texas A&M University, College Station, Texas, United States of America.

SARS-CoV-2 is a single stranded RNA (ssRNA) virus and contains GU-rich sequences distributed abundantly in the genome. In COVID-19, the infection and immune hyperactivation causes accumulation of inflammatory immune cells, blood clots, and protein aggregates in lung fluid, increased lung alveolar wall thickness, and upregulation of serum cytokine levels. A serum protein called serum amyloid P (SAP) has a calming effect on the innate immune system and shows efficacy as a therapeutic for fibrosis in animal models and clinical trials. Here we show that aspiration of the GU-rich ssRNA oligonucleotide ORN06 into mouse lungs induces all of the above COVID-19-like symptoms. Men tend to have more severe COVID-19 symptoms than women, and in the aspirated ORN06 model, male mice tended to have more severe symptoms than female mice. Intraperitoneal injections of SAP starting from day 1 post ORN06 aspiration attenuated the ORN06-induced increase in the number of inflammatory cells and formation of clot-like aggregates in the mouse lung fluid, reduced ORN06-increased alveolar wall thickness and accumulation of exudates in the alveolar airspace, and attenuated an ORN06-induced upregulation of the inflammatory cytokines IL-1β, IL-6, IL-12p70, IL-23, and IL-27 in serum. SAP also reduced D-dimer levels in the lung fluid. In human peripheral blood mononuclear cells, SAP attenuated ORN06-induced extracellular accumulation of IL-6. Together, these results suggest that aspiration of ORN06 is a simple model for both COVID-19 as well as cytokine storm in general, and that SAP is a potential therapeutic for diseases with COVID-19-like symptoms and/or a cytokine storm.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245924PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822324PMC
February 2021

A CD209 ligand and a sialidase inhibitor differentially modulate adipose tissue and liver macrophage populations and steatosis in mice on the Methionine and Choline-Deficient (MCD) diet.

PLoS One 2020 30;15(12):e0244762. Epub 2020 Dec 30.

Department of Biology, Texas A&M University, College Station, TX, United States of America.

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes and is characterized by the accumulation of fat in the liver (steatosis). NAFLD can transition into non-alcoholic steatohepatitis (NASH), with liver cell injury, inflammation, and an increased risk of fibrosis. We previously found that injections of either 1866, a synthetic ligand for the lectin receptor CD209, or DANA, a sialidase inhibitor, can inhibit inflammation and fibrosis in multiple animal models. The methionine and choline-deficient (MCD) diet is a model of NASH which results in the rapid induction of liver steatosis and inflammation. In this report, we show that for C57BL/6 mice on a MCD diet, injections of both 1866 and DANA reversed MCD diet-induced decreases in white fat, decreases in adipocyte size, and white fat inflammation. However, these effects were not observed in type 2 diabetic db/db mice on a MCD diet. In db/db mice on a MCD diet, 1866 decreased liver steatosis, but these effects were not observed in C57BL/6 mice. There was no correlation between the ability of 1866 or DANA to affect steatosis and the effects of these compounds on the density of liver macrophage cells expressing CLEC4F, CD64, F4/80, or Mac2. Together these results indicate that 1866 and DANA modulate adipocyte size and adipose tissue macrophage populations, that 1866 could be useful for modulating steatosis, and that changes in the local density of 4 different liver macrophages cell types do not correlate with effects on liver steatosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244762PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773271PMC
March 2021

Polyphosphate is an extracellular signal that can facilitate bacterial survival in eukaryotic cells.

Proc Natl Acad Sci U S A 2020 12 2;117(50):31923-31934. Epub 2020 Dec 2.

Department of Biology, Texas A&M University, College Station, TX 77843-3474

Polyphosphate is a linear chain of phosphate residues and is present in organisms ranging from bacteria to humans. Pathogens such as accumulate polyphosphate, and reduced expression of the polyphosphate kinase that synthesizes polyphosphate decreases their survival. How polyphosphate potentiates pathogenicity is poorly understood. K-12 do not accumulate detectable levels of extracellular polyphosphate and have poor survival after phagocytosis by or human macrophages. In contrast, and accumulate detectable levels of extracellular polyphosphate, and have relatively better survival after phagocytosis by or macrophages. Adding extracellular polyphosphate increased survival after phagocytosis by and macrophages. Reducing expression of polyphosphate kinase 1 in reduced extracellular polyphosphate and reduced survival in and macrophages, and this was reversed by the addition of extracellular polyphosphate. Conversely, treatment of and macrophages with recombinant yeast exopolyphosphatase reduced the survival of phagocytosed or cells lacking the putative polyphosphate receptor GrlD had reduced sensitivity to polyphosphate and, compared to wild-type cells, showed increased killing of phagocytosed and Polyphosphate inhibited phagosome acidification and lysosome activity in and macrophages and reduced early endosomal markers in macrophages. Together, these results suggest that bacterial polyphosphate potentiates pathogenicity by acting as an extracellular signal that inhibits phagosome maturation.
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http://dx.doi.org/10.1073/pnas.2012009117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749317PMC
December 2020

Inhibiting Sialidase-Induced TGF-1 Activation Attenuates Pulmonary Fibrosis in Mice.

J Pharmacol Exp Ther 2021 01 3;376(1):106-117. Epub 2020 Nov 3.

Departments of Biology (T.R.K., R.H.G.) and Biochemistry and Biophysics (T.D.M.), Texas A&M University, College Station, Texas

The active form of transforming growth factor-1 (TGF-1) plays a key role in potentiating fibrosis. TGF-1 is sequestered in an inactive state by a latency-associated glycopeptide (LAP). Sialidases (also called neuraminidases (NEU)) cleave terminal sialic acids from glycoconjugates. The sialidase NEU3 is upregulated in fibrosis, and mice lacking Neu3 show attenuated bleomycin-induced increases in active TGF-1 in the lungs and attenuated pulmonary fibrosis. Here we observe that recombinant human NEU3 upregulates active human TGF-1 by releasing active TGF-1 from its latent inactive form by desialylating LAP. Based on the proposed mechanism of action of NEU3, we hypothesized that compounds with a ring structure resembling picolinic acid might be transition state analogs and thus possible NEU3 inhibitors. Some compounds in this class showed nanomolar IC for recombinant human NEU3 releasing active human TGF-1 from the latent inactive form. The compounds given as daily 0.1-1-mg/kg injections starting at day 10 strongly attenuated lung inflammation, lung TGF-1 upregulation, and pulmonary fibrosis at day 21 in a mouse bleomycin model of pulmonary fibrosis. These results suggest that NEU3 participates in fibrosis by desialylating LAP and releasing TGF-1 and that the new class of NEU3 inhibitors are potential therapeutics for fibrosis. SIGNIFICANCE STATEMENT: The extracellular sialidase NEU3 appears to be a key driver of pulmonary fibrosis. The significance of this report is that 1) we show the mechanism (NEU3 desialylates the latency-associated glycopeptide protein that keeps the profibrotic cytokine transforming growth factor-1 (TGF-β1) in an inactive state, causing active TGF-β1 release), 2) we then use the predicted NEU3 mechanism to identify nM IC NEU3 inhibitors, and 3) these new NEU3 inhibitors are potent therapeutics in a mouse model of pulmonary fibrosis.
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http://dx.doi.org/10.1124/jpet.120.000258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788355PMC
January 2021

High-Fat Diet-Induced Adipose Tissue and Liver Inflammation and Steatosis in Mice Are Reduced by Inhibiting Sialidases.

Am J Pathol 2021 01 8;191(1):131-143. Epub 2020 Oct 8.

Department of Biology, Texas A&M University, College Station, Texas. Electronic address:

High-fat diet (HFD)-induced inflammation and steatosis of adipose tissue and liver are associated with a variety of serious health risks. Sialic acids are found as the distal terminal sugar on glycoproteins, which are removed by sialidases (neuraminidases). In humans and mice, pulmonary fibrosis is associated with up-regulation of sialidases, and injections of sialidase inhibitors attenuate bleomycin-induced pulmonary fibrosis. Sialidase levels are altered in obese rodents and humans. This report shows that for mice on an HFD, injections of the sialidase inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid inhibit weight gain, reduce steatosis, and decrease adipose tissue and liver inflammation. Compared with control, mice lacking the sialidase neuraminidase 3 have reduced HFD-induced adipose tissue and liver inflammation. These data suggest that sialidases promote adipose and liver inflammation in response to a high-fat diet.
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http://dx.doi.org/10.1016/j.ajpath.2020.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786079PMC
January 2021

Serum Amyloid P inhibits single stranded RNA-induced lung inflammation, lung damage, and cytokine storm in mice.

bioRxiv 2020 Aug 27. Epub 2020 Aug 27.

SARS-CoV-2 is a single stranded RNA (ssRNA) virus and contains GU-rich sequences distributed abundantly in the genome. In COVID-19, the infection and immune hyperactivation causes accumulation of inflammatory immune cells, blood clots, and protein aggregates in lung fluid, increased lung alveolar wall thickness, and upregulation of serum cytokine levels. A serum protein called serum amyloid P (SAP) has a calming effect on the innate immune system and shows efficacy as a therapeutic for fibrosis in animal models and clinical trials. In this report, we show that aspiration of the GU-rich ssRNA oligonucleotide ORN06 into mouse lungs induces all of the above COVID-19-like symptoms. Men tend to have more severe COVID-19 symptoms than women, and in the aspirated ORN06 model, male mice tended to have more severe symptoms than female mice. Intraperitoneal injections of SAP starting from day 1 post ORN06 aspiration attenuated the ORN06-induced increase in the number of inflammatory cells and formation of clot-like aggregates in the mouse lung fluid, reduced ORN06-increased alveolar wall thickness and accumulation of exudates in the alveolar airspace, and attenuated an ORN06-induced upregulation of the inflammatory cytokines IL-1β, IL-6, IL-12p70, IL-23, and IL-27 in serum. Together, these results suggest that aspiration of ORN06 is a simple model for both COVID-19 as well as cytokine storm in general, and that SAP is a potential therapeutic for diseases with COVID-19-like symptoms as well as diseases that generate a cytokine storm.
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http://dx.doi.org/10.1101/2020.08.26.269183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457621PMC
August 2020

Reduced Sialylation and Bioactivity of the Antifibrotic Protein Serum Amyloid P in the Sera of Patients with Idiopathic Pulmonary Fibrosis.

Immunohorizons 2020 06 23;4(6):352-362. Epub 2020 Jun 23.

Department of Biology, Texas A&M University, College Station, TX 77843; and

Pulmonary fibrosis is a chronic and generally fatal disorder characterized by progressive formation of scar-like tissue in the lungs. Sialic acids are often found as the terminal sugar on extracellular glycoconjugates such as protein glycosylations. Sialidases, also known as neuraminidases, desialylate glycoconjugates. Serum amyloid P (SAP), a pentameric serum glycoprotein that has two sialic acids on each polypeptide, inhibits the differentiation of monocytes into fibrocytes and promotes human PBMCs to accumulate high extracellular levels of IL-10. When SAP is desialylated with sialidase, the effects of SAP on fibrocyte differentiation and IL-10 accumulation are strongly inhibited. Intriguingly, in patients with pulmonary fibrosis, there are increased levels of sialidase activity in the bronchoalveolar lavage fluid, increased levels of sialidases in the lungs, and decreased levels of SAP in the sera. To elucidate the role of SAP desialylation in idiopathic pulmonary fibrosis (IPF) pathogenesis, we purified SAP from the serum of IPF patients and healthy controls and measured the extent of sialylation and bioactivity of the purified SAP. We find that some IPF patients have abnormally high levels of the sialidase NEU3 in their sera and that the SAP in the sera of IPF patients has an abnormally high extent of desialylation and an abnormally low ability to inhibit fibrocyte differentiation and induce extracellular IL-10 accumulation by PBMC. These results suggest that SAP desialylation may play a role in IPF pathogenesis and that inhibiting NEU3 could be a potential therapeutic target for IPF.
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http://dx.doi.org/10.4049/immunohorizons.2000043DOI Listing
June 2020

TGF-β1 increases sialidase 3 expression in human lung epithelial cells by decreasing its degradation and upregulating its translation.

Exp Lung Res 2020 Apr - May;46(3-4):75-80. Epub 2020 Feb 26.

Department of Biology, Texas A&M University, College Station, Texas, USA.

We previously found extensive desialylation of glycoconjugates and upregulation of the sialidase enzyme NEU3 in fibrotic lesions in human and mouse lungs. However, studies using microarray analysis of whole lung tissue mRNA and single cell RNA-seq found no significant difference in levels of mRNA between IPF patients and controls. This study aimed to elucidate how NEU3 was upregulated in fibrotic lungs. Transforming growth factor-β1 (TGF-β1), a key driver of fibrosis, was added to A549 human alveolar basal epithelial adenocarcinoma cells and human small airway epithelial cells (HSAEpC). NEU3 expression in A549 cells and HSAEpC was detected by immunofluorescence staining. NEU3 translation and degradation were assessed by polysome profiling (polysomes efficiently translate mRNAs; monosomes poorly translate mRNAs) and cycloheximide chase after treating cells with or without TGF-β1 for 48 h. TGF-β1 increased NEU3 expression and secretion in A549 cells and HSAEpC but did not change total (nuclear + cytosolic) mRNA levels. TGF-β1 decreased the degradation rate of NEU3 in A549 cells. TGF-β1 decreased mRNA levels in monosomes and increased mRNA level in polysomes. TGF-β1 upregulates levels of NEU3 in epithelial cells by both decreasing NEU3 degradation and by increasing the translation of mRNA, explaining the apparent paradox of high levels of NEU3 protein in pulmonary fibrosis without a concomitant increase in the expression of mRNA.
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http://dx.doi.org/10.1080/01902148.2020.1733135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164658PMC
February 2020

Fibrocytes in the Tumor Microenvironment.

Adv Exp Med Biol 2020 ;1224:79-85

Department of Biology/ILSB, Texas A&M University, College Station, TX, USA.

Tumors have long been compared to chronic wounds that do not heal, since they share many of the same molecular and cellular processes. In normal wounds, healing processes lead to restoration of cellular architecture, while in malignant tumors, these healing processes become dysregulated and contribute to growth and invasion of neoplastic cells into the surrounding tissues. Fibrocytes are fibroblast-like cells that differentiate from bone marrow-derived CD14 circulating monocytes and aid wound healing. Although most monocytes will differentiate into macrophages after extravasating into a tissue, signals present in a wound environment can cause some monocytes to differentiate into fibrocytes. The fibrocytes secrete matrix proteins and inflammatory cytokines, activate local fibroblasts to proliferate and increase extracellular matrix production, and promote angiogenesis, and because fibrocytes are contractile, they also help wound contraction. There is now emerging evidence that fibrocytes are present in the tumor microenvironment, attracted by the chronic tissue damage and cytokines from both cancer cells and other immune cells. Fibrocytes may aid in the survival and spread of neoplastic cells, so these wound-healing cells may be a promising target for anticancer research in future studies.
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http://dx.doi.org/10.1007/978-3-030-35723-8_6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212529PMC
February 2020

An improved shotgun antisense method for mutagenesis and gene identification.

Biotechniques 2020 03 24;68(3):163-165. Epub 2020 Jan 24.

Department of Biology, Texas A&M University, College Station, TX 77843, USA.

Shotgun expression of antisense cDNA, where each transformed cell expresses a different antisense cDNA, has been used for mutagenesis and gene identification in . However, the method has two limitations. First, there were too few clones in the shotgun antisense cDNA library to have an antisense cDNA for every gene in the genome. Second, the unequal transcription level of genes resulted in many antisense cDNAs in the library for some genes but relatively few antisense cDNAs for other genes. Here we report an improved method for generating a larger antisense cDNA library with a reduced percentage of cDNA clones from highly prevalent mRNAs and demonstrate its utility by screening for signal transduction pathway components in .
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http://dx.doi.org/10.2144/btn-2019-0123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092706PMC
March 2020

Extracellular signaling in Dictyostelium.

Int J Dev Biol 2019 ;63(8-9-10):395-405

Department of Biology, Texas A∧M University, College Station, Texas, USA.

In the last few decades, we have learned a considerable amount about how eukaryotic cells communicate with each other, and what it is the cells are telling each other. The simplicity of Dictyostelium discoideum, and the wide variety of available tools to study this organism, makes it the equivalent of a hydrogen atom for cell and developmental biology. Studies using Dictyostelium have pioneered a good deal of our understanding of eukaryotic cell communication. In this review, we will present a brief overview of how Dictyostelium cells use extracellular signals to attract each other, repel each other, sense their local cell density, sense whether the nearby cells are starving or stressed, count themselves to organize the formation of structures containing a regulated number of cells, sense the volume they are in, and organize their multicellular development. Although we are probably just beginning to learn what the cells are telling each other, the elucidation of Dictyostelium extracellular signals has already led to the development of possible therapeutics for human diseases.
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http://dx.doi.org/10.1387/ijdb.190259rgDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986813PMC
July 2020

Attenuated pulmonary fibrosis in sialidase-3 knockout () mice.

Am J Physiol Lung Cell Mol Physiol 2020 01 16;318(1):L165-L179. Epub 2019 Oct 16.

Department of Biology, Texas A&M University, College Station, Texas.

Pulmonary fibrosis involves the formation of inappropriate scar tissue in the lungs, but what drives fibrosis is unclear. Sialidases (also called neuraminidases) cleave terminal sialic acids from glycoconjugates. In humans and mice, pulmonary fibrosis is associated with desialylation of glycoconjugates and upregulation of sialidases. Of the four mammalian sialidases, we previously detected only NEU3 in the bronchoalveolar lavage fluid from mice with bleomycin-induced pulmonary fibrosis. In this report, we show that NEU3 upregulates extracellular accumulation of the profibrotic cytokines IL-6 and IL-1β, and IL-6 upregulates NEU3 in human peripheral blood mononuclear cells, suggesting that NEU3 may be part of a positive feedback loop potentiating fibrosis. To further elucidate the role of NEU3 in fibrosis, we used bleomycin to induce lung fibrosis in wild-type C57BL/6 and mice. At 21 days after bleomycin, compared with male and female C57BL/6 mice, male and female mice had significantly less inflammation, less upregulation of other sialidases and the profibrotic cytokine active transforming growth factor β1, and less fibrosis in the lungs. Our results suggest that NEU3 participates in fibrosis and that NEU3 could be a target to develop treatments for fibrosis.
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http://dx.doi.org/10.1152/ajplung.00275.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985870PMC
January 2020

Serum Amyloid P and a Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin Ligand Inhibit High-Fat Diet-Induced Adipose Tissue and Liver Inflammation and Steatosis in Mice.

Am J Pathol 2019 12 18;189(12):2400-2413. Epub 2019 Sep 18.

Department of Biology, Texas A&M University, College Station, Texas. Electronic address:

High-fat diet (HFD)-induced inflammation is associated with a variety of health risks. The systemic pentraxin serum amyloid P (SAP) inhibits inflammation. SAP activates the high-affinity IgG receptor Fcγ receptor I (FcγRI; CD64) and the lectin receptor dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN; CD209). Herein, we show that for mice on an HFD, injections of SAP and a synthetic CD209 ligand (1866) reduced HFD-increased adipose and liver tissue inflammation, adipocyte differentiation, and lipid accumulation in adipose tissue. HFD worsened glucose tolerance test results and caused increased adipocyte size; for mice on an HFD, SAP improved glucose tolerance test results and reduced adipocyte size. Mice on an HFD had elevated serum levels of IL-1β, IL-23, interferon (IFN)-β, IFN-γ, monocyte chemoattractant protein 1 [MCP-1; chemokine (C-C motif) ligand 2 (CCL2)], and tumor necrosis factor-α. SAP reduced serum levels of IL-23, IFN-β, MCP-1, and tumor necrosis factor-α, whereas 1866 reduced IFN-γ. In vitro, SAP, but not 1866, treated cells isolated from white fat tissue (stromal vesicular fraction) produced the anti-inflammatory cytokine IL-10. HFD causes steatosis, and both SAP and 1866 reduced it. Conversely, compared with control mice, SAP knockout mice fed on a normal diet had increased white adipocyte cell sizes, increased numbers of inflammatory cells in adipose and liver tissue, and steatosis; and these effects were exacerbated on an HFD. SAP and 1866 may inhibit some, but not all, of the effects of a high-fat diet.
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http://dx.doi.org/10.1016/j.ajpath.2019.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902115PMC
December 2019

The Use of Diffusion Calculations and Monte Carlo Simulations to Understand the Behavior of Cells in Communities.

Authors:
Richard H Gomer

Comput Struct Biotechnol J 2019 8;17:684-688. Epub 2019 Jun 8.

Department of Biology, Texas A&M University, College Station, TX 77843-3474, USA.

Microbial communities are the simplest possible model of multicellular tissues, allowing studies of cell-cell interactions to be done with as few extraneous factors as possible. For instance, the eukaryotic microbe proliferates as single cells, and when starved, the cells aggregate together and form structures of ~20,000 cells. The cells use a variety of signals to direct their movement, inform each other of their local cell density and whether they are starving, and organize themselves into groups of ~20,000 cells. Mathematical models and computational approaches have been a key check on, and guide of, the experimental work. In this minireview, I will discuss diffusion calculations and Monte Carlo simulations that were used for studies that offer general paradigms for several aspects of cell-cell communication. For instance, computational work showed that diffusible secreted cell-density sensing (quorum) factors can diffuse away so quickly from a single cell that the local concentration will not build up to incorrectly cause the cell to sense that it is in the presence of a high density of other cells secreting that signal. In another example, computation correctly predicted a mechanism that allows a group of cells to break up into subgroups. These are thus some examples of the power and necessity of computational work in biology.
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http://dx.doi.org/10.1016/j.csbj.2019.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603294PMC
June 2019

Extracellular Polyphosphate Promotes Macrophage and Fibrocyte Differentiation, Inhibits Leukocyte Proliferation, and Acts as a Chemotactic Agent for Neutrophils.

J Immunol 2019 07 3;203(2):493-499. Epub 2019 Jun 3.

Department of Biology, Texas A&M University, College Station, TX 77843

Fibrocytes are monocyte-derived fibroblast like cells that participate in wound healing, but little is known about what initiates fibrocyte differentiation. Blood platelets contain 60-100-mer polymers of phosphate groups called polyphosphate, and when activated, platelets induce blood clotting (the first step in wound healing) in part by the release of polyphosphate. We find that activated platelets release a factor that promotes fibrocyte differentiation. The factor is abolished by treating the crude platelet factor with the polyphosphate-degrading enzyme polyphosphatase, and polyphosphate promotes fibrocyte differentiation. Macrophages and recruited neutrophils also potentiate wound healing, and polyphosphate also promotes macrophage differentiation and induces chemoattraction of neutrophils. In support of the hypothesis that polyphosphate is a signal that affects leukocytes, we observe saturable binding of polyphosphate to these cells. Polyphosphate also inhibits leukocyte proliferation and proteasome activity. These results suggest new roles for extracellular polyphosphate as a mediator of wound healing and inflammation and also provide a potential link between platelet activation and the progression of fibrosing diseases.
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http://dx.doi.org/10.4049/jimmunol.1801559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615990PMC
July 2019

Serum Amyloid P Component Binds Fungal Surface Amyloid and Decreases Human Macrophage Phagocytosis and Secretion of Inflammatory Cytokines.

mBio 2019 03 12;10(2). Epub 2019 Mar 12.

Department of Medicine, University of Arizona, Tucson, Arizona, USA

In patients with invasive fungal diseases, there is often little cellular inflammatory response. We tested the idea that binding of the human constitutive plasma protein serum amyloid P component (SAP) (also called PTX2) to dampens the innate immune response to this fungus. Many pathogenic fungi have cell surface amyloid-like structures important for adhesion and biofilm formation. Human SAP bound to fungi that expressed functional cell surface amyloid, but SAP had minimal binding to fungi with reduced expression of cell surface amyloid. In the absence of SAP, phagocytosis of fungi by human macrophages was potentiated by expression of amyloid on the fungi. SAP binding to fungi inhibited their phagocytosis by macrophages. Macrophages pretreated with SAP displayed reduced fungal phagocytosis, reduced secretion of inflammatory cytokines (IFN-γ, IL-6, and TNF-α), and increased secretion of the anti-inflammatory cytokine IL-10. SAP bound to fungi or added to the medium upregulated the expression of the anti-inflammatory receptor CD206 on macrophages. These findings suggest that SAP bound to amyloid-like structures on fungal cells dampens the host cellular immune response in fungal diseases such as invasive candidiasis. Macrophages are a key part of our innate immune system and are responsible for recognizing invading microbes, ingesting them, and sending appropriate signals to other immune cells. We have found that human macrophages can recognize invading yeast pathogens that have a specific molecular pattern of proteins on their surfaces: these proteins have structures similar to the structures of amyloid aggregates in neurodegenerative diseases like Alzheimer's disease. However, this surface pattern also causes the fungi to bind a serum protein called serum amyloid P component (SAP). In turn, the SAP-coated yeasts are poorly recognized and seldom ingested by the macrophages, and the macrophages have a more tolerant and less inflammatory response in the presence of SAP. Therefore, we find that surface structures on the yeast can alter how the macrophages react to invading microbes.
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http://dx.doi.org/10.1128/mBio.00218-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414697PMC
March 2019

The putative G protein-coupled receptor GrlD mediates extracellular polyphosphate sensing in Dictyostelium discoideum.

Mol Biol Cell 2019 04 20;30(9):1118-1128. Epub 2019 Feb 20.

Department of Biology, Texas A&M University, College Station, TX 77843-3474.

Five or more orthophosphates bound together by high-energy phosphoanhydride bonds are highly ubiquitous inorganic molecules called polyphosphate. Polyphosphate acts as a signaling molecule eliciting a number of responses in eukaryotic cells, but the mechanisms mediating these effects are poorly understood. Proliferating Dictyostelium discoideum cells accumulate extracellular polyphosphate. At extracellular concentrations similar to those observed in stationary phase cells, polyphosphate inhibits proteasome activity and proliferation, and induces aggregation. Here we identify GrlD as a putative G protein-coupled receptor that mediates binding of extracellular polyphosphate to the cell surface. Cells lacking GrlD do not respond to polyphosphate-induced proteasome inhibition, aggregation, or proliferation inhibition. Polyphosphate also elicits differential effects on cell-substratum adhesion and cytoskeletal F-actin levels based on nutrient availability, and these effects were also mediated by GrlD. Starving cells also accumulate extracellular polyphosphate. Starved cells treated with exopolyphosphatase failed to aggregate effectively, suggesting that polyphosphate also acts as a signaling molecule during starvation-induced development of Dictyostelium. Together, these results suggest that a eukaryotic cell uses a G protein-coupled receptor to mediate the sensing and response to extracellular polyphosphate.
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http://dx.doi.org/10.1091/mbc.E18-10-0686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724513PMC
April 2019

Different Isoforms of the Neuronal Guidance Molecule Slit2 Directly Cause Chemoattraction or Chemorepulsion of Human Neutrophils.

J Immunol 2019 01 3;202(1):239-248. Epub 2018 Dec 3.

Department of Biology, Texas A&M University, College Station, TX 77843-3474

The movement of neutrophils between blood and tissues appears to be regulated by chemoattractants and chemorepellents. Compared with neutrophil chemoattractants, relatively little is known about neutrophil chemorepellents. Slit proteins are endogenously cleaved into a variety of N- and C-terminal fragments, and these fragments are neuronal chemorepellents and inhibit chemoattraction of many cell types, including neutrophils. In this report, we show that the ∼140-kDa N-terminal Slit2 fragment (Slit2-N) is a chemoattractant and the ∼110-kDa N-terminal Slit2 fragment (Slit2-S) is a chemorepellent for human neutrophils. The effects of both Slit2 fragments were blocked by Abs to the Slit2 receptor Roundabout homolog 1 or the Slit2 coreceptor Syndecan-4. Slit2-N did not appear to activate Ras but increased phosphatidylinositol 3,4,5-triphosphate levels. Slit2-N-induced chemoattraction was unaffected by Ras inhibitors, reversed by PI3K inhibitors, and blocked by Cdc42 and Rac inhibitors. In contrast, Slit2-S activated Ras but did not increase phosphatidylinositol 3,4,5-triphosphate levels. Slit2-S-induced chemorepulsion was blocked by Ras and Rac inhibitors, not affected by PI3K inhibitors, and reversed by Cdc42 inhibitors. Slit2-N, but not Slit2-S, increased neutrophil adhesion, myosin L chain 2 phosphorylation, and polarized actin formation and single pseudopods at the leading edge of cells. Slit2-S induced multiple pseudopods. These data suggest that Slit2 isoforms use similar receptors but different intracellular signaling pathways and have different effects on the cytoskeleton and pseudopods to induce neutrophil chemoattraction or chemorepulsion.
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http://dx.doi.org/10.4049/jimmunol.1800681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310129PMC
January 2019

An endogenous chemorepellent directs cell movement by inhibiting pseudopods at one side of cells.

Mol Biol Cell 2019 01 21;30(2):242-255. Epub 2018 Nov 21.

Department of Biology, Texas A&M University, College Station, TX 77843-3474.

Eukaryotic chemoattraction signal transduction pathways, such as those used by Dictyostelium discoideum to move toward cAMP, use a G protein-coupled receptor to activate multiple conserved pathways such as PI3 kinase/Akt/PKB to induce actin polymerization and pseudopod formation at the front of a cell, and PTEN to localize myosin II to the rear of a cell. Relatively little is known about chemorepulsion. We previously found that AprA is a chemorepellent protein secreted by Dictyostelium cells. Here we used 29 cell lines with disruptions of cAMP and/or AprA signal transduction pathway components, and delineated the AprA chemorepulsion pathway. We find that AprA uses a subset of chemoattraction signal transduction pathways including Ras, protein kinase A, target of rapamycin (TOR), phospholipase A, and ERK1, but does not require the PI3 kinase/Akt/PKB and guanylyl cyclase pathways to induce chemorepulsion. Possibly as a result of not using the PI3 kinase/Akt/PKB pathway and guanylyl cyclases, AprA does not induce actin polymerization or increase the pseudopod formation rate, but rather appears to inhibit pseudopod formation at the side of cells closest to the source of AprA.
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http://dx.doi.org/10.1091/mbc.E18-09-0562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589559PMC
January 2019

The Development of Serum Amyloid P as a Possible Therapeutic.

Front Immunol 2018 16;9:2328. Epub 2018 Oct 16.

Department of Biology, Texas A&M University, College Station, TX, United States.

Pentraxins such as serum amyloid P (SAP; also known as PTX2) regulate several aspects of the innate immune system. SAP inhibits the differentiation of monocyte-derived fibroblast-like cells called fibrocytes, promotes the formation of immuno-regulatory macrophages, and inhibits neutrophil adhesion to extracellular matrix proteins. In this minireview, we describe how these effects of SAP have led to its possible use as a therapeutic, and how modulating SAP effects might be used for other therapeutics. Fibrosing diseases such as pulmonary fibrosis, cardiac fibrosis, liver fibrosis, and renal fibrosis are associated with 30-45% of deaths in the US. Fibrosis involves both fibrocyte differentiation and profibrotic macrophage differentiation, and possibly because SAP inhibits both of these processes, in 9 different animal models, SAP inhibited fibrosis. In Phase 1B and Phase 2 clinical trials, SAP injections reduced the decline in lung function in pulmonary fibrosis patients, and in a small Phase 2 trial SAP injections reduced fibrosis in myelofibrosis patients. Acute respiratory distress syndrome/ acute lung injury (ARDS/ALI) involves the accumulation of neutrophils in the lungs, and possibly because SAP inhibits neutrophil adhesion, SAP injections reduced the severity of ARDS in an animal model. Conversely, depleting SAP is a potential therapeutic for amyloidosis, topically removing SAP from wound fluid speeds wound healing in animal models, and blocking SAP binding to one of its receptors makes cultured macrophages more aggressive toward tuberculosis bacteria. These results suggest that modulating pentraxin signaling might be useful for a variety of diseases.
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http://dx.doi.org/10.3389/fimmu.2018.02328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232687PMC
October 2019

An Autocrine Proliferation Repressor Regulates Proliferation and Chemorepulsion Using the G Protein-Coupled Receptor GrlH.

mBio 2018 02 13;9(1). Epub 2018 Feb 13.

Department of Biology, Texas A&M University, College Station, Texas, USA

In eukaryotic microbes, little is known about signals that inhibit the proliferation of the cells that secrete the signal, and little is known about signals (chemorepellents) that cause cells to move away from the source of the signal. Autocrine proliferation repressor protein A (AprA) is a protein secreted by the eukaryotic microbe AprA is a chemorepellent for and inhibits the proliferation of We previously found that cells sense AprA using G proteins, suggesting the existence of a G protein-coupled AprA receptor. To identify the AprA receptor, we screened mutants lacking putative G protein-coupled receptors. We found that, compared to the wild-type strain, cells lacking putative receptor GrlH ( cells) show rapid proliferation, do not have large numbers of cells moving away from the edges of colonies, are insensitive to AprA-induced proliferation inhibition and chemorepulsion, and have decreased AprA binding. Expression of GrlH in cells ( ) rescues the phenotypes described above. These data indicate that AprA signaling may be mediated by GrlH in Little is known about how eukaryotic cells can count themselves and thus regulate the size of a tissue or density of cells. In addition, little is known about how eukaryotic cells can sense a repellant signal and move away from the source of the repellant, for instance, to organize the movement of cells in a developing embryo or to move immune cells out of a tissue. In this study, we found that a eukaryotic microbe uses G protein-coupled receptors to mediate both cell density sensing and chemorepulsion.
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http://dx.doi.org/10.1128/mBio.02443-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821085PMC
February 2018

Protease activated-receptor 2 is necessary for neutrophil chemorepulsion induced by trypsin, tryptase, or dipeptidyl peptidase IV.

J Leukoc Biol 2018 01 11;103(1):119-128. Epub 2017 Dec 11.

Department of Biology, Texas A&M University, College Station, Texas, USA.

Compared to neutrophil chemoattractants, relatively little is known about the mechanism neutrophils use to respond to chemorepellents. We previously found that the soluble extracellular protein dipeptidyl peptidase IV (DPPIV) is a neutrophil chemorepellent. In this report, we show that an inhibitor of the protease activated receptor 2 (PAR2) blocks DPPIV-induced human neutrophil chemorepulsion, and that PAR2 agonists such as trypsin, tryptase, 2f-LIGRL, SLIGKV, and AC55541 induce human neutrophil chemorepulsion. Several PAR2 agonists in turn block the ability of the chemoattractant fMLP to attract neutrophils. Compared to neutrophils from male and female C57BL/6 mice, neutrophils from male and female mice lacking PAR2 are insensitive to the chemorepulsive effects of DPPIV or PAR2 agonists. Acute respiratory distress syndrome (ARDS) involves an insult-mediated influx of neutrophils into the lungs. In a mouse model of ARDS, aspiration of PAR2 agonists starting 24 h after an insult reduce neutrophil numbers in the bronchoalveolar lavage (BAL) fluid, as well as the post-BAL lung tissue. Together, these results indicate that the PAR2 receptor mediates DPPIV-induced chemorepulsion, and that PAR2 agonists might be useful to induce neutrophil chemorepulsion.
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http://dx.doi.org/10.1002/JLB.3A0717-308RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383205PMC
January 2018

Dietary NaCl affects bleomycin-induced lung fibrosis in mice.

Exp Lung Res 2017 Nov - Dec;43(9-10):395-406. Epub 2017 Dec 8.

a Department of Biology , Texas A&M University , College Station , TX , USA.

Purpose: High levels of NaCl in the diet are associated with both cardiac and renal fibrosis, but whether salt intake affects pulmonary fibrosis has not been examined.

Aim Of The Study: To test the hypothesis that salt intake might affect pulmonary fibrosis.

Materials And Methods: Mice were fed low, normal, or high salt diets for 2 weeks, and then treated with oropharyngeal bleomycin to induce pulmonary fibrosis, or oropharyngeal saline as a control.

Results: As determined by collagen staining of lung sections, and protein levels and cell numbers in the bronchoalveolar lavage (BAL) fluid at 21 days after bleomycin, the high salt diet did not exacerbate bleomycin-induced fibrosis, while the low salt diet attenuated fibrosis. For the bleomycin-treated mice, staining of the post-BAL lung sections indicated that compared to the regular salt diet, high salt increased the number of Ly6c-positive macrophages and decreased the number of CD11c and CD206-positive macrophages and dendritic cells. The low salt diet caused bleomycin-induced leukocyte numbers to be similar to control saline-treated mice, but reduced numbers of CD45/collagen-VI positive fibrocytes. In the saline controls, low dietary salt decreased CD11b and CD11c positive cells in lung sections, and high dietary salt increased fibrocytes.

Conclusions: Together, these data suggest the possibility that a low salt diet might attenuate pulmonary fibrosis.
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http://dx.doi.org/10.1080/01902148.2017.1385110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004787PMC
August 2018

C-reactive protein (CRP) but not the related pentraxins serum amyloid P and PTX3 inhibits the proliferation and induces apoptosis of the leukemia cell line Mono Mac 6.

BMC Immunol 2017 Dec 4;18(1):47. Epub 2017 Dec 4.

Department of Biology, Texas A&M University, College Station, TX, 77843-3474, USA.

Background: Pentraxins are a family of highly conserved secreted proteins that regulate the innate immune system, including monocytes and macrophages. C-reactive protein (CRP) is a plasma protein whose levels can rise to 1000 μg/ml from the normal <3 μg/ ml during inflammation.

Results: We find that CRP inhibits proliferation of the human myeloid leukemia cell line Mono Mac 6 with an IC50 of 75 μg/ ml by inducing apoptosis of these cells. The related proteins serum amyloid P (SAP) and pentraxin 3 (PTX3) do not inhibit Mono Mac 6 proliferation. CRP has no significant effect on the proliferation of other leukemia cell lines such as HL-60, Mono Mac 1, K562, U937, or THP-1, or the survival of normal peripheral blood cells. The effect of CRP appears to be dependent on the CRP receptor FcγRI, and is negatively regulated by a phosphatidylinositol -3-kinase pathway.

Conclusion: These data reveal differential signaling by pentraxins on immune cells, and suggest that CRP can regulate the proliferation of some myeloid leukemia cells.
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http://dx.doi.org/10.1186/s12865-017-0230-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716379PMC
December 2017

Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model.

Sci Rep 2017 11 8;7(1):15069. Epub 2017 Nov 8.

Department of Biology, Texas A&M University, 301 Old Main Drive, College Station, Texas, 77843-3474, USA.

Fibrosis involves increasing amounts of scar tissue appearing in a tissue, but what drives this is unclear. In fibrotic lesions in human and mouse lungs, we found extensive desialylation of glycoconjugates, and upregulation of sialidases. The fibrosis-associated cytokine TGF-β1 upregulates sialidases in human airway epithelium cells, lung fibroblasts, and immune system cells. Conversely, addition of sialidases to human peripheral blood mononuclear cells induces accumulation of extracellular TGF-β1, forming what appears to be a sialidase - TGF-β1 - sialidase positive feedback loop. Monocyte-derived cells called fibrocytes also activate fibroblasts, and we found that sialidases potentiate fibrocyte differentiation. A sialylated glycoprotein called serum amyloid P (SAP) inhibits fibrocyte differentiation, and sialidases attenuate SAP function. Injections of the sialidase inhibitors DANA and oseltamivir (Tamiflu) starting either 1 day or 10 days after bleomycin strongly attenuate pulmonary fibrosis in the mouse bleomycin model, and by breaking the feedback loop, cause a downregulation of sialidase and TGF-β1 accumulation. Together, these results suggest that a positive feedback loop involving sialidases potentiates fibrosis, and suggest that sialidase inhibitors could be useful for the treatment of fibrosis.
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http://dx.doi.org/10.1038/s41598-017-15198-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678159PMC
November 2017

Identification of compounds that decrease numbers of in human macrophages in the presence of serum amyloid P.

J Leukoc Biol 2017 09 2;102(3):857-869. Epub 2017 Aug 2.

Department of Biology, Texas A&M University, College Station, Texas, USA

Mϕs are a heterogeneous population of cells and include classically activated Mϕs (M1) and alternatively activated Mϕs (M2). Mϕs can change from M1 to M2 and vice versa in response to environmental stimuli. Serum amyloid P (SAP) is a constitutive plasma protein that polarizes Mϕs to an M2 phenotype, and part of this effect is mediated through FcγRI receptors. In an effort to find ways to alter Mϕs phenotypes, we screened for compounds that can block the SAP-FcγRI interaction. From a screen of 3000 compounds, we found 12 compounds that reduced the ability of fluorescently labeled human SAP to bind cells expressing human FcγRI. Based on cell surface marker expression, 8 of the compounds inhibited the effect of SAP on skewing human Mϕs to an M2 phenotype and in the presence of SAP polarized Mϕs to an M1 phenotype. In diseases, such as tuberculosis, M1s are more effective at killing bacteria than M2s. SAP potentiated the numbers of the mycobacterial strains and in Mϕs. When added along with SAP, 2 of the compounds reduced intracellular numbers. Together, these results indicate that the blocking of SAP effects on Mϕs can skew these cells toward an M1 phenotype, and this may be useful in treating diseases, such as tuberculosis.
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http://dx.doi.org/10.1189/jlb.1A0317-118RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608052PMC
September 2017

Monocyte differentiation and macrophage priming are regulated differentially by pentraxins and their ligands.

BMC Immunol 2017 06 15;18(1):30. Epub 2017 Jun 15.

Department of Biology, Texas A&M University, 3474 TAMU, College Station, TX, 77843-3474, USA.

Background: Circulating bone marrow-derived monocytes can leave the blood, enter a tissue, and differentiate into M1 inflammatory, M2a remodeling/fibrotic, or M2c/Mreg resolving/immune-regulatory macrophages. Macrophages can also convert from one of the above types to another. Pentraxins are secreted proteins that bind to, and promote efficient clearance of, microbial pathogens and cellular debris during infection, inflammation, and tissue damage. The pentraxins C-reactive protein (CRP), serum amyloid P (SAP), and pentraxin-3 (PTX3) can also bind a variety of endogenous ligands. As monocytes and macrophages are exposed to differing concentrations of pentraxins and their ligands during infection, inflammation, and tissue damage, we assessed what effect pentraxins and their ligands have on these cells.

Results: We found that many polarization markers do not discriminate between the effects of pentraxins and their ligands on macrophages. However, pentraxins, their ligands, and cytokines differentially regulate the expression of the hemoglobin-haptoglobin complex receptor CD163, the sialic acid-binding lectin CD169, and the macrophage mannose receptor CD206. CRP, a pentraxin generally thought of as being pro-inflammatory, increases the extracellular accumulation of the anti-inflammatory cytokine IL-10, and this effect is attenuated by GM-CSF, mannose-binding lectin, and factor H.

Conclusions: These results suggest that the presence of pentraxins and their ligands regulate macrophage differentiation in the blood and tissues, and that CRP may be a potent inducer of the anti-inflammatory cytokine IL-10.
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http://dx.doi.org/10.1186/s12865-017-0214-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472910PMC
June 2017

Extracellular polyphosphate signals through Ras and Akt to prime cells for development.

J Cell Sci 2017 Jul 5;130(14):2394-2404. Epub 2017 Jun 5.

Department of Biology, Texas A&M University, College Station, TX 77843-3474, USA

Linear chains of five to hundreds of phosphates called polyphosphate are found in organisms ranging from bacteria to humans, but their function is poorly understood. In , polyphosphate is used as a secreted signal that inhibits cytokinesis in an autocrine negative feedback loop. To elucidate how cells respond to this unusual signal, we undertook a proteomic analysis of cells treated with physiological levels of polyphosphate and observed that polyphosphate causes cells to decrease levels of actin cytoskeleton proteins, possibly explaining how polyphosphate inhibits cytokinesis. Polyphosphate also causes proteasome protein levels to decrease, and in both and human leukemia cells, decreases proteasome activity and cell proliferation. Polyphosphate also induces cells to begin development by increasing expression of the cell-cell adhesion molecule CsA (also known as CsaA) and causing aggregation, and this effect, as well as the inhibition of proteasome activity, is mediated by Ras and Akt proteins. Surprisingly, Ras and Akt do not affect the ability of polyphosphate to inhibit proliferation, suggesting that a branching pathway mediates the effects of polyphosphate, with one branch affecting proliferation, and the other branch affecting development.
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http://dx.doi.org/10.1242/jcs.203372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536921PMC
July 2017

Functional similarities between the dictyostelium protein AprA and the human protein dipeptidyl-peptidase IV.

Protein Sci 2017 03 15;26(3):578-585. Epub 2017 Feb 15.

Department of Biology, Texas A&M University, College Station, Texas.

Autocrine proliferation repressor protein A (AprA) is a protein secreted by Dictyostelium discoideum cells. Although there is very little sequence similarity between AprA and any human protein, AprA has a predicted structural similarity to the human protein dipeptidyl peptidase IV (DPPIV). AprA is a chemorepellent for Dictyostelium cells, and DPPIV is a chemorepellent for neutrophils. This led us to investigate if AprA and DPPIV have additional functional similarities. We find that like AprA, DPPIV is a chemorepellent for, and inhibits the proliferation of, D. discoideum cells, and that AprA binds some DPPIV binding partners such as fibronectin. Conversely, rAprA has DPPIV-like protease activity. These results indicate a functional similarity between two eukaryotic chemorepellent proteins with very little sequence similarity, and emphasize the usefulness of using a predicted protein structure to search a protein structure database, in addition to searching for proteins with similar sequences.
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http://dx.doi.org/10.1002/pro.3107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326566PMC
March 2017