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https://www.readbyqxmd.com/read/29866797/epithelial-and-endothelial-pannexin1-channels-mediate-aki
#1
Jakub Jankowski, Heather M Perry, Christopher B Medina, Liping Huang, Junlan Yao, Amandeep Bajwa, Ulrike M Lorenz, Diane L Rosin, Kodi S Ravichandran, Brant E Isakson, Mark D Okusa
Background Pannexin1 (Panx1), an ATP release channel, is present in most mammalian tissues, but the role of Panx1 in health and disease is not fully understood. Panx1 may serve to modulate AKI; ATP is a precursor to adenosine and may function to block inflammation, or ATP may act as a danger-associated molecular pattern and initiate inflammation. Methods We used pharmacologic and genetic approaches to evaluate the effect of Panx1 on kidney ischemia-reperfusion injury (IRI), a mouse model of AKI. Results Pharmacologic inhibition of gap junctions, including Panx1, by administration of carbenoxolone protected mice from IRI...
June 4, 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29745255/pannexin-1-channels-on-endothelial-cells-mediate-vascular-inflammation-during-lung-ischemia-reperfusion-injury
#2
Ashish K Sharma, Eric J Charles, Yunge Zhao, Adishesh K Narahari, Pranav K Baderdinni, Miranda E Good, Ulrike M Lorenz, Irving L Kron, Douglas A Bayliss, Kodi S Ravichandran, Brant E Isakson, Victor E Laubach
Ischemia-reperfusion injury (IRI), which involves inflammation, vascular permeability, and edema, remains a major challenge after lung transplantation. Pannexin 1 (Panx1) channels modulate cellular ATP release during inflammation. This study tests the hypothesis that endothelial Panx1 is a key mediator of vascular inflammation and edema after IR and that IRI can be blocked by Panx1 antagonism. A murine hilar ligation model of IRI was utilized whereby left lungs underwent 1 hour of ischemia and 2 hours of reperfusion...
May 10, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/29454661/rethinking-phagocytes-clues-from-the-retina-and-testes
#3
REVIEW
Kristen K Penberthy, Jeffrey J Lysiak, Kodi S Ravichandran
Specialized phagocytes are a newly appreciated classification of phagocyte that currently encompasses Sertoli cells (SCs) of the testes and the retinal pigment epithelial cells (RPE) of the retina. While these cells support very different tissues, they have a striking degree of similarity both as phagocytes and in ways that go beyond cell clearance. The clearance of apoptotic germ cells, cell debris, and used photoreceptor outer segments are critical functions of these cells, and the unique nature of their clearance events make specialized phagocytes uniquely suited for studying the larger implications of cell clearance in vivo...
April 2018: Trends in Cell Biology
https://www.readbyqxmd.com/read/29288236/cd47-blockade-as-an-adjuvant-immunotherapy-for-resectable-pancreatic-cancer
#4
Alex D Michaels, Timothy E Newhook, Sara J Adair, Sho Morioka, Bernadette J Goudreau, Sarbajeet Nagdas, Matthew G Mullen, Jesse B Persily, Timothy N J Bullock, Craig L Slingluff, Kodi S Ravichandran, J Thomas Parsons, Todd W Bauer
Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only 2 years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival. Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by (i) depleting mouse macrophages in nude mice with liposomal clodronate injection, and (ii) injecting tumor cells into nude versus NOD- scid -gamma mice...
March 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29237722/pannexin-1-channels-as-an-unexpected-new-target-of-the-anti-hypertensive-drug-spironolactone
#5
Miranda E Good, Yu-Hsin Chiu, Ivan K H Poon, Christopher B Medina, Joshua T Butcher, Suresh K Mendu, Leon J DeLalio, Alexander W Lohman, Norbert Leitinger, Eugene Barrett, Ulrike M Lorenz, Bimal N Desai, Iris Z Jaffe, Douglas A Bayliss, Brant E Isakson, Kodi S Ravichandran
RATIONALE: Resistant hypertension is a major health concern with unknown cause. Spironolactone is an effective antihypertensive drug, especially for patients with resistant hypertension, and is considered by the World Health Organization as an essential medication. Although spironolactone can act at the mineralocorticoid receptor (MR; NR3C2), there is increasing evidence of MR-independent effects of spironolactone. OBJECTIVE: Here, we detail the unexpected discovery that Panx1 (pannexin 1) channels could be a relevant in vivo target of spironolactone...
February 16, 2018: Circulation Research
https://www.readbyqxmd.com/read/29116131/context-dependent-compensation-among-phosphatidylserine-recognition-receptors
#6
Kristen K Penberthy, Claudia Rival, Laura S Shankman, Michael H Raymond, Jianye Zhang, Justin S A Perry, Chang Sup Lee, Claudia Z Han, Suna Onengut-Gumuscu, Krzysztof Palczewski, Jeffrey J Lysiak, Kodi S Ravichandran
Phagocytes express multiple phosphatidylserine (PtdSer) receptors that recognize apoptotic cells. It is unknown whether these receptors are interchangeable or if they play unique roles during cell clearance. Loss of the PtdSer receptor Mertk is associated with apoptotic corpse accumulation in the testes and degeneration of photoreceptors in the eye. Both phenotypes are linked to impaired phagocytosis by specialized phagocytes: Sertoli cells and the retinal pigmented epithelium (RPE). Here, we overexpressed the PtdSer receptor BAI1 in mice lacking MerTK (Mertk -/- Bai1 Tg ) to evaluate PtdSer receptor compensation in vivo...
November 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28267764/ex-vivo-modulation-of-the-foxo1-phosphorylation-state-does-not-lead-to-dysfunction-of-t-regulatory-cells
#7
Kristen Kelley Penberthy, Monica Weaver Buckley, Sanja Arandjelovic, Kodi Ravichandran
Peripheral regulatory CD4+ T cells (Treg cells) prevent maladaptive inflammatory responses to innocuous foreign antigens. Treg cell dysfunction has been linked to many inflammatory diseases, including allergic airway inflammation. Glucocorticoids that are used to treat allergic airway inflammation and asthma are thought to work in part by promoting Treg cell differentiation; patients who are refractory to these drugs have defective induction of anti-inflammatory Treg cells. Previous observations suggest that Treg cells deficient in the transcription factor FoxO1 are pro-inflammatory, and that FoxO1 activity is regulated by its phosphorylation status and nuclear localization...
2017: PloS One
https://www.readbyqxmd.com/read/28195232/hematopoietic-pannexin-1-function-is-critical-for-neuropathic-pain
#8
Janelle L Weaver, Sanja Arandjelovic, Gregory Brown, Suresh K Mendu, Michael S Schappe, Monica W Buckley, Yu-Hsin Chiu, Shaofang Shu, Jin K Kim, Joyce Chung, Julia Krupa, Vesna Jevtovic-Todorovic, Bimal N Desai, Kodi S Ravichandran, Douglas A Bayliss
Neuropathic pain symptoms respond poorly to available therapeutics, with most treated patients reporting unrelieved pain and significant impairment in daily life. Here, we show that Pannexin 1 (Panx1) in hematopoietic cells is required for pain-like responses following nerve injury in mice, and a potential therapeutic target. Panx1 knockout mice (Panx1-/- ) were protected from hypersensitivity in two sciatic nerve injury models. Bone marrow transplantation studies show that expression of functional Panx1 in hematopoietic cells is necessary for mechanical hypersensitivity following nerve injury...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28134257/a-quantized-mechanism-for-activation-of-pannexin-channels
#9
Yu-Hsin Chiu, Xueyao Jin, Christopher B Medina, Susan A Leonhardt, Volker Kiessling, Brad C Bennett, Shaofang Shu, Lukas K Tamm, Mark Yeager, Kodi S Ravichandran, Douglas A Bayliss
Pannexin 1 (PANX1) subunits form oligomeric plasma membrane channels that mediate nucleotide release for purinergic signalling, which is involved in diverse physiological processes such as apoptosis, inflammation, blood pressure regulation, and cancer progression and metastasis. Here we explore the mechanistic basis for PANX1 activation by using wild type and engineered concatemeric channels. We find that PANX1 activation involves sequential stepwise sojourns through multiple discrete open states, each with unique channel gating and conductance properties that reflect contributions of the individual subunits of the hexamer...
January 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28118592/embryonic-trogocytosis-neighborly-nibbling-during-development
#10
Justin S A Perry, Kodi S Ravichandran
New work in Caenorhabditis elegans shows that during embryogenesis endodermal cells interact with and regulate primordial germ cells by actively excising and digesting germ cell lobes. Endodermal cells utilize proteins linked to endocytosis to perform this unique 'cannibalistic' process.
January 23, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/27832495/adhesion-gpcrs-as-modulators-of-immune-cell-function
#11
REVIEW
Jörg Hamann, Cheng-Chih Hsiao, Chang Sup Lee, Kodi S Ravichandran, Hsi-Hsien Lin
Immune cells express several adhesion G protein-coupled receptors (aGPCRs), including the ADGRE subfamily members EMR1 (F4/80, ADGRE1), EMR2 (ADGRE2), EMR3 (ADGRE3), EMR4 (FIRE, ADGRE4), and CD97 (ADGRE5), the ADGRB subfamily member BAI1 (ADGRB1), and the ADGRG subfamily members GPR56 (ADGRG1), GPR97 (Pb99, ADGRG3), and GPR114 (ADGRG5). Expression of these molecules in hematopoietic stem and progenitor cells, monocytes/macrophages (Mφs), dendritic cells, granulocytes, and lymphocytes depends on lineage diversification and maturation, making them suitable markers for individual leukocyte subsets (e...
2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27820945/macrophages-redirect-phagocytosis-by-non-professional-phagocytes-and-influence-inflammation
#12
Claudia Z Han, Ignacio J Juncadella, Jason M Kinchen, Monica W Buckley, Alexander L Klibanov, Kelly Dryden, Suna Onengut-Gumuscu, Uta Erdbrügger, Stephen D Turner, Yun M Shim, Kenneth S Tung, Kodi S Ravichandran
Professional phagocytes (such as macrophages) and non-professional phagocytes (such as epithelial cells) clear billions of apoptotic cells and particles on a daily basis. Although professional and non-professional macrophages reside in proximity in most tissues, whether they communicate with each other during cell clearance, and how this might affect inflammation, is not known. Here we show that macrophages, through the release of a soluble growth factor and microvesicles, alter the type of particles engulfed by non-professional phagocytes and influence their inflammatory response...
November 24, 2016: Nature
https://www.readbyqxmd.com/read/27558816/clearance-of-dying-cells-by-phagocytes-mechanisms-and-implications-for-disease-pathogenesis
#13
REVIEW
Aaron M Fond, Kodi S Ravichandran
The efficient clearance of apoptotic cells is an evolutionarily conserved process crucial for homeostasis in multicellular organisms. The clearance involves a series of steps that ultimately facilitates the recognition of the apoptotic cell by the phagocytes and the subsequent uptake and processing of the corpse. These steps include the phagocyte sensing of "find-me" signals released by the apoptotic cell, recognizing "eat-me" signals displayed on the apoptotic cell surface, and then intracellular signaling within the phagocyte to mediate phagocytic cup formation around the corpse and corpse internalization, and the processing of the ingested contents...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27459067/the-dynamics-of-apoptotic-cell-clearance
#14
REVIEW
Michael R Elliott, Kodi S Ravichandran
The phagocytic clearance of dying cells in a tissue is a highly orchestrated series of intercellular events coordinated by a complex signaling network. Recent data from genetic, biochemical, and live-imaging approaches have greatly enhanced our understanding of the dynamics of cell clearance and how the process is orchestrated at the cellular and tissue levels. We discuss how networks regulating apoptotic cell clearance are integrated to enable a rapid, efficient, and high-capacity clearance system within tissues...
July 25, 2016: Developmental Cell
https://www.readbyqxmd.com/read/27345468/-this-way-please-apoptotic-cells-regulate-phagocyte-migration-before-and-after-engulfment
#15
COMMENT
Amiram Ariel, Kodi S Ravichandran
Apoptotic leukocyte clearance is a hallmark of the resolution of inflammation and is a central fate-determining event for macrophages. The directional migration of motile phagocytes toward cellular corpses and the subsequent engulfment are tightly regulated, and the exciting molecular mechanisms for these complex steps are actively under investigation. In this issue Angsana et al. [Eur. J. Immunol. 2016. 46: 1592-1599.] report that the chemokine receptor CXCR4 is upregulated on murine and human macrophages following the engulfment of apoptotic cells, or following exposure to the pro-resolving nucleotide adenosine...
July 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27313577/how-mouse-macrophages-sense-what-is-going-on
#16
REVIEW
Klaus Ley, Akula Bala Pramod, Michael Croft, Kodi S Ravichandran, Jenny P Ting
Macrophages are central to both innate and adaptive immunity. With few exceptions, macrophages are the first cells that sense trouble and respond to disturbances in almost all tissues and organs. They sense their environment, inhibit or kill pathogens, take up apoptotic and necrotic cells, heal tissue damage, and present antigens to T cells. Although the origins (yolk sac versus monocyte-derived) and phenotypes (functions, gene expression profiles, surface markers) of macrophages vary between tissues, they have many receptors in common that are specific to one or a few molecular species...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27037190/boosting-apoptotic-cell-clearance-by-colonic-epithelial-cells-attenuates-inflammation-in-vivo
#17
Chang Sup Lee, Kristen K Penberthy, Karen M Wheeler, Ignacio J Juncadella, Peter Vandenabeele, Jeffrey J Lysiak, Kodi S Ravichandran
Few apoptotic corpses are seen even in tissues with high cellular turnover, leading to the notion that the capacity for engulfment in vivo is vast. Whether corpse clearance can be enhanced in vivo for potential benefit is not known. In a colonic inflammation model, we noted that the expression of the phagocytic receptor Bai1 was progressively downmodulated. Consistent with this, BAI1-deficient mice had more pronounced colitis and lower survival, with many uncleared apoptotic corpses and inflammatory cytokines within the colonic epithelium...
April 19, 2016: Immunity
https://www.readbyqxmd.com/read/26838550/the-adhesion-gpcr-bai1-mediates-macrophage-ros-production-and-microbicidal-activity-against-gram-negative-bacteria
#18
Emily A Billings, Chang Sup Lee, Katherine A Owen, Ryan S D'Souza, Kodi S Ravichandran, James E Casanova
The detection of microbes and initiation of an innate immune response occur through pattern recognition receptors (PRRs), which are critical for the production of inflammatory cytokines and activation of the cellular microbicidal machinery. In particular, the production of reactive oxygen species (ROS) by the NADPH oxidase complex is a critical component of the macrophage bactericidal machinery. We previously characterized brain-specific angiogenesis inhibitor 1 (BAI1), a member of the adhesion family of G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs), as a PRR that mediates the selective phagocytic uptake of Gram-negative bacteria by macrophages...
February 2, 2016: Science Signaling
https://www.readbyqxmd.com/read/26683144/apoptotic-cell-recognition-receptors-and-scavenger-receptors
#19
REVIEW
Kristen K Penberthy, Kodi S Ravichandran
Phosphatidylserine recognition receptors are a highly diverse set of receptors grouped by their ability to recognize the 'eat-me' signal phosphatidylserine on apoptotic cells. Most of the phosphatidylserine recognition receptors dampen inflammation by inducing the production of anti-inflammatory mediators during the phagocytosis of apoptotic corpses. However, many phosphatidylserine receptors are also capable of recognizing other ligands, with some receptors being categorized as scavenger receptors. It is now appreciated that these receptors can elicit different downstream events for particular ligands...
January 2016: Immunological Reviews
https://www.readbyqxmd.com/read/26287597/phagocytosis-of-apoptotic-cells-in-homeostasis
#20
REVIEW
Sanja Arandjelovic, Kodi S Ravichandran
Human bodies collectively turn over about 200 billion to 300 billion cells every day. Such turnover is an integral part of embryonic and postnatal development, as well as routine tissue homeostasis. This process involves the induction of programmed cell death in specific cells within the tissues and the specific recognition and removal of dying cells by a clearance 'crew' composed of professional, non-professional and specialized phagocytes. In the past few years, considerable progress has been made in identifying many features of apoptotic cell clearance...
September 2015: Nature Immunology
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