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• W2902399144 abstract "Platelet-leukocyte interactions promote acute glomerulonephritis. However, neither the nature of the interactions between platelets and immune cells nor the capacity of platelets to promote leukocyte activation has been characterized in this condition. We used confocal intravital microscopy to define the interactions of platelets with neutrophils, monocytes, and endothelial cells in glomerular capillaries in mice. In the absence of inflammation, platelets underwent rapid on/off interactions with immune cells. During glomerulonephritis induced by in situ immune complex formation, platelets that interacted with neutrophils or monocytes, but not with other intraglomerular cells, were retained in the glomerulus for prolonged durations. Depletion of platelets inhibited both neutrophil recruitment and activation. Inhibition of platelet activating factor reduced neutrophil recruitment without impacting reactive oxygen species generation, while blocking CXC chemokine ligand 7 (CXCL7) reduced both responses. In contrast, inhibition of the adenosine diphosphate and thromboxane A2 pathways inhibited neutrophil reactive oxygen species generation without affecting neutrophil adhesion. Thus, platelet retention in glomerular capillaries following immune complex deposition stems from prolongation of platelet interactions with immune cells but not other substrates. Pro-inflammatory mediators play divergent roles in promoting neutrophil retention and activation in glomerular capillaries. Platelet-leukocyte interactions promote acute glomerulonephritis. However, neither the nature of the interactions between platelets and immune cells nor the capacity of platelets to promote leukocyte activation has been characterized in this condition. We used confocal intravital microscopy to define the interactions of platelets with neutrophils, monocytes, and endothelial cells in glomerular capillaries in mice. In the absence of inflammation, platelets underwent rapid on/off interactions with immune cells. During glomerulonephritis induced by in situ immune complex formation, platelets that interacted with neutrophils or monocytes, but not with other intraglomerular cells, were retained in the glomerulus for prolonged durations. Depletion of platelets inhibited both neutrophil recruitment and activation. Inhibition of platelet activating factor reduced neutrophil recruitment without impacting reactive oxygen species generation, while blocking CXC chemokine ligand 7 (CXCL7) reduced both responses. In contrast, inhibition of the adenosine diphosphate and thromboxane A2 pathways inhibited neutrophil reactive oxygen species generation without affecting neutrophil adhesion. Thus, platelet retention in glomerular capillaries following immune complex deposition stems from prolongation of platelet interactions with immune cells but not other substrates. Pro-inflammatory mediators play divergent roles in promoting neutrophil retention and activation in glomerular capillaries. In many forms of glomerular disease, leukocytes recruited to the glomerulus promote inflammation and glomerular dysfunction.1Kitching A.R. Hutton H.L. The players: cells involved in glomerular disease.Clin J Am Soc Nephrol. 2016; 11: 1664-1674Google Scholar Leukocyte recruitment to the glomerular capillaries does not follow the conventional paradigm involving an initial rolling step as a prerequisite for adhesion, with subsequent progression to transmigration.2Kuligowski M.P. Kitching A.R. Hickey M.J. Leukocyte recruitment to the inflamed glomerulus: a critical role for platelet-derived P-selectin in the absence of rolling.J Immunol. 2006; 176: 6991-6999Google Scholar, 3Devi S. Kuligowski M.P. Kwan R.Y. et al.Platelet recruitment to the inflamed glomerulus occurs via an alphaIIbbeta3/GPVI-dependent pathway.Am J Pathol. 2010; 177: 1131-1142Google Scholar In contrast, immune cells arrest without rolling and are retained within the glomerular microvasculature, from where they mediate injurious effects.4Devi S. Li A. Westhorpe C.L. et al.Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus.Nat Med. 2013; 19: 107-112Google Scholar, 5Finsterbusch M. Hall P. Li A. et al.Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus.Proc Natl Acad Sci U S A. 2016; 113: E5172-E5181Google Scholar, 6Nishi H. Furuhashi K. Cullere X. et al.Neutrophil FcgammaRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases.J Clin Invest. 2017; 127: 3810-3826Google Scholar, 7Westhorpe C.L. Bayard J.E. O'Sullivan K.M. et al.In vivo imaging of inflamed glomeruli reveals dynamics of neutrophil extracellular trap formation in glomerular capillaries.Am J Pathol. 2017; 187: 318-331Google Scholar In vivo imaging has shown that, in response to inflammatory stimuli, neutrophils and monocytes undergo prolonged retention and migration in the glomerular capillaries, during which time neutrophils can generate injurious reactive oxygen species (ROS).4Devi S. Li A. Westhorpe C.L. et al.Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus.Nat Med. 2013; 19: 107-112Google Scholar, 5Finsterbusch M. Hall P. Li A. et al.Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus.Proc Natl Acad Sci U S A. 2016; 113: E5172-E5181Google Scholar Platelets also accumulate in inflamed glomerular capillaries.2Kuligowski M.P. Kitching A.R. Hickey M.J. Leukocyte recruitment to the inflamed glomerulus: a critical role for platelet-derived P-selectin in the absence of rolling.J Immunol. 2006; 176: 6991-6999Google Scholar, 8Johnson R.J. Alpers C.E. Pritzl P. et al.Platelets mediate neutrophil-dependent immune complex nephritis in the rat.J Clin Invest. 1988; 82: 1225-1235Google Scholar, 9Johnson R.J. Alpers C.E. Pruchno C. et al.Mechanisms and kinetics for platelet and neutrophil localization in immune complex nephritis.Kidney Int. 1989; 36: 780-789Google Scholar, 10Poelstra K. Hardonk M.J. Koudstaal J. et al.Intraglomerular platelet aggregation and experimental glomerulonephritis.Kidney Int. 1990; 37: 1500-1508Google Scholar, 11Mahan J.D. Hebert L.A. McAllister C. et al.Platelet involvement in experimental immune complex-mediated glomerulonephritis in the nonhuman primate.Kidney Int. 1993; 44: 716-725Google Scholar In hemolytic uremic syndrome and lupus nephritis, occlusive platelet thrombi are commonly observed and are sometimes associated with fibrin deposition.12Ruggenenti P. Noris M. Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura.Kidney Int. 2001; 60: 831-846Google Scholar, 13Song D. Wu L.H. Wang F.M. et al.The spectrum of renal thrombotic microangiopathy in lupus nephritis.Arthritis Res Ther. 2013; 15: R12Google Scholar In patients with glomerulonephritis, observations such as glomerular platelet accumulation, reduced platelet life span, and increased platelet secretory products in the circulation have implicated platelets as contributors to disease, a contention supported by findings from animal models.2Kuligowski M.P. Kitching A.R. Hickey M.J. Leukocyte recruitment to the inflamed glomerulus: a critical role for platelet-derived P-selectin in the absence of rolling.J Immunol. 2006; 176: 6991-6999Google Scholar, 8Johnson R.J. Alpers C.E. Pritzl P. et al.Platelets mediate neutrophil-dependent immune complex nephritis in the rat.J Clin Invest. 1988; 82: 1225-1235Google Scholar, 9Johnson R.J. Alpers C.E. Pruchno C. et al.Mechanisms and kinetics for platelet and neutrophil localization in immune complex nephritis.Kidney Int. 1989; 36: 780-789Google Scholar, 14Barnes J.L. Platelets in glomerular disease.Nephron. 1997; 77: 378-393Google Scholar, 15Ideura T. Ogasawara M. Tomura S. et al.Effect of thrombocytopenia on the onset of immune complex glomerulonephritis.Nephron. 1992; 60: 49-55Google Scholar, 16Hirahashi J. Hishikawa K. Kaname S. et al.Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury.Circulation. 2009; 120: 1255-1265Google Scholar However, in some of these studies, platelet accumulation involves either nonocclusive platelet aggregation or an absence of histologically detectable platelet deposition. The latter findings raise questions as to the dynamics of platelet interactions in the high shear environment of the glomerulus.11Mahan J.D. Hebert L.A. McAllister C. et al.Platelet involvement in experimental immune complex-mediated glomerulonephritis in the nonhuman primate.Kidney Int. 1993; 44: 716-725Google Scholar, 14Barnes J.L. Platelets in glomerular disease.Nephron. 1997; 77: 378-393Google Scholar Platelets are active contributors to a wide variety of inflammatory responses. In addition to their recognized involvement in cardiovascular diseases, platelets play proinflammatory roles in conditions such as acute lung injury, rheumatoid arthritis, inflammatory bowel disease, and autoimmune cerebral inflammation.17Smyth S.S. McEver R.P. Weyrich A.S. et al.Platelet functions beyond hemostasis.J Thromb Haemost. 2009; 7: 1759-1766Google Scholar, 18Setianto B.Y. Hartopo A.B. Gharini P.P. et al.Circulating soluble CD40 ligand mediates the interaction between neutrophils and platelets in acute coronary syndrome.Heart Vessels. 2010; 25: 282-287Google Scholar, 19Wang Y. Sakuma M. Chen Z. et al.Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac-1 is critical for the biological response to vascular injury.Circulation. 2005; 112: 2993-3000Google Scholar, 20Zarbock A. Singbartl K. Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation.J Clin Invest. 2006; 116: 3211-3219Google Scholar, 21Boilard E. Nigrovic P.A. Larabee K. et al.Platelets amplify inflammation in arthritis via collagen-dependent microparticle production.Science. 2010; 327: 580-583Google Scholar, 22Bunescu A. Seideman P. Lenkei R. et al.Enhanced Fcgamma receptor I, alphaMbeta2 integrin receptor expression by monocytes and neutrophils in rheumatoid arthritis: interaction with platelets.J Rheumatol. 2004; 31: 2347-2355Google Scholar, 23Irving P.M. Macey M.G. Feakins R.M. et al.Platelet-leucocyte aggregates form in the mesenteric vasculature in patients with ulcerative colitis.Eur J Gastroenterol Hepatol. 2008; 20: 283-289Google Scholar, 24Pamuk G.E. Vural O. Turgut B. et al.Increased circulating platelet-neutrophil, platelet-monocyte complexes, and platelet activation in patients with ulcerative colitis: a comparative study.Am J Hematol. 2006; 81: 753-759Google Scholar, 25Langer H.F. Choi E.Y. Zhou H. et al.Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis.Circ Res. 2012; 110: 1202-1210Google Scholar One of the mechanisms underlying this effect is promotion of leukocyte recruitment and activation. Via their expression of adhesion molecules including P-selectin, glycoprotein Ib, and integrin αIIbβ3, platelets attached to the endothelium can act as a substrate for leukocyte adhesion.26Zuchtriegel G. Uhl B. Puhr-Westerheide D. et al.Platelets guide leukocytes to their sites of extravasation.PLoS Biol. 2016; 14: e1002459Google Scholar, 27Carvalho-Tavares J. Hickey M.J. Hutchison J. et al.A role for platelets and endothelial selectins in tumor necrosis factor-alpha-induced leukocyte recruitment in the brain microvasculature.Circ Res. 2000; 87: 1141-1148Scopus (193) Google Scholar, 28Schulz C. Schafer A. Stolla M. et al.Chemokine fractalkine mediates leukocyte recruitment to inflammatory endothelial cells in flowing whole blood: a critical role for P-selectin expressed on activated platelets.Circulation. 2007; 116: 764-773Google Scholar, 29Asaduzzaman M. Lavasani S. Rahman M. et al.Platelets support pulmonary recruitment of neutrophils in abdominal sepsis.Crit Care Med. 2009; 37: 1389-1396Google Scholar, 30Ghasemzadeh M. Kaplan Z.S. Alwis I. et al.The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi.Blood. 2013; 121: 4555-4566Google Scholar, 31Lalor P.F. Herbert J. Bicknell R. et al.Hepatic sinusoidal endothelium avidly binds platelets in an integrin-dependent manner, leading to platelet and endothelial activation and leukocyte recruitment.Am J Physiol Gastrointest Liver Physiol. 2013; 304: G469-G478Google Scholar, 32Slaba I. Wang J. Kolaczkowska E. et al.Imaging the dynamic platelet-neutrophil response in sterile liver injury and repair in mice.Hepatology. 2015; 62: 1593-1605Google Scholar Platelets also release mediators capable of inducing leukocyte adhesion and migration, promote leukocyte activation via contact-dependent mechanisms, and can also stimulate endothelial activation.30Ghasemzadeh M. Kaplan Z.S. Alwis I. et al.The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi.Blood. 2013; 121: 4555-4566Google Scholar, 33Schenk B.I. Petersen F. Flad H.D. et al.Platelet-derived chemokines CXC chemokine ligand (CXCL)7, connective tissue-activating peptide III, and CXCL4 differentially affect and cross-regulate neutrophil adhesion and transendothelial migration.J Immunol. 2002; 169: 2602-2610Google Scholar, 34Pitchford S. Pan D. Welch H.C. Platelets in neutrophil recruitment to sites of inflammation.Curr Opin Hematol. 2017; 24: 23-31Google Scholar, 35Weyrich A.S. Elstad M.R. McEver R.P. et al.Activated platelets signal chemokine synthesis by human monocytes.J Clin Invest. 1996; 97: 1525-1534Google Scholar, 36Piccardoni P. Sideri R. Manarini S. et al.Platelet/polymorphonuclear leukocyte adhesion: a new role for SRC kinases in Mac-1 adhesive function triggered by P-selectin.Blood. 2001; 98: 108-116Google Scholar, 37Evangelista V. Pamuklar Z. Piccoli A. et al.Src family kinases mediate neutrophil adhesion to adherent platelets.Blood. 2007; 109: 2461-2469Google Scholar, 38Henn V. Slupsky J.R. Grafe M. et al.CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.Nature. 1998; 391: 591-594Google Scholar These observations reveal that the mechanisms whereby platelets promote leukocyte recruitment and activation can vary widely according to the inflammatory context. In the glomerulus during an acute inflammatory response, we have observed that platelets serve as the major source of P-selectin, an adhesion molecule important for glomerular neutrophil recruitment.2Kuligowski M.P. Kitching A.R. Hickey M.J. Leukocyte recruitment to the inflamed glomerulus: a critical role for platelet-derived P-selectin in the absence of rolling.J Immunol. 2006; 176: 6991-6999Google Scholar Consistent with this, removal of platelets reduces neutrophil accumulation and leads to attenuation of neutrophil-dependent glomerular injury, as determined by assessment of proteinuria during the first 24 hours after injury. Conversely, elimination of neutrophils also reduces platelet accumulation, indicating a complex interdependence in the intraglomerular interactions of these cell types.3Devi S. Kuligowski M.P. Kwan R.Y. et al.Platelet recruitment to the inflamed glomerulus occurs via an alphaIIbbeta3/GPVI-dependent pathway.Am J Pathol. 2010; 177: 1131-1142Google Scholar To understand these interactions, we previously used in vivo imaging to detect fluorescently labeled platelets transferred into recipient animals.3Devi S. Kuligowski M.P. Kwan R.Y. et al.Platelet recruitment to the inflamed glomerulus occurs via an alphaIIbbeta3/GPVI-dependent pathway.Am J Pathol. 2010; 177: 1131-1142Google Scholar While this study identified roles for glycoprotein VI and the αIIbβ3/fibrinogen/intercellular adhesion molecule 1 pathway in glomerular platelet accumulation, the imaging approach used precluded visualization of endogenous platelets or simultaneous assessment of platelets and neutrophils. The advent of rapid frame-rate spinning disk confocal intravital microscopy (SD-IVM) has overcome these shortcomings leading to the discovery of novel actions of platelets in other vascular beds.39Wong C.H. Jenne C.N. Petri B. et al.Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance.Nat Immunol. 2013; 14: 785-792Google Scholar, 40Sreeramkumar V. Adrover J.M. Ballesteros I. et al.Neutrophils scan for activated platelets to initiate inflammation.Science. 2014; 346: 1234-1238Google Scholar The aims of this study were to use this approach to investigate the interactions of platelets, neutrophils, and monocytes in the acutely inflamed glomerulus and to identify platelet-derived mediators that promote neutrophil recruitment and activation under these conditions. To detect endogenous platelets in vivo, we used a previously validated antibody-based approach and 2 forms of intravital microscopy.39Wong C.H. Jenne C.N. Petri B. et al.Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance.Nat Immunol. 2013; 14: 785-792Google Scholar, 41Jenne C.N. Wong C.H. Petri B. et al.The use of spinning-disk confocal microscopy for the intravital analysis of platelet dynamics in response to systemic and local inflammation.PLoS One. 2011; 6e25109Google Scholar In initial experiments using multiphoton microscopy to examine intact kidneys of LysM–enhanced green fluorescent protein (EGFP) mice, individual circulating platelets underwent frequent on-off interactions in the uninflamed glomerular microvasculature (Figure 1a, Supplementary Movie S1). This occurred via contacts with both neutrophils and in areas where no neutrophils were present. To characterize the dynamics of these events in greater detail, we utilized high frame rate SD-IVM, examining glomeruli in post-hydronephrotic kidneys. Under steady-state conditions, circulating platelets underwent interactions in the glomerular microvasculature, both with neutrophils and other cells including endothelial cells (Figure 1b, Supplementary Movie S2). We found 30 to 40 platelets/min adhered in each glomerulus, typically via “touch-and-go” interactions (Figure 1b–d, Supplementary Movie S2). The duration of these interactions (referred to as dwell time) was predominantly <5 seconds. Moreover, platelet aggregates were extremely rare, suggesting little or no activation of platelets under steady-state conditions. Approximately 30% of platelets retained in glomerular capillaries did so via interactions with neutrophils (Figure 1e). These findings demonstrate that in the absence of inflammation, platelets undergo tethering in the glomerular microvasculature, interacting with neutrophils, endothelial cells, and potentially other intravascular cells. Given the greater spatial and temporal resolution of platelet imaging experiments in post-hydronephrotic kidneys, all subsequent intravital microscopy experiments were performed using this approach. To investigate whether intraglomerular platelet interactions were altered in acute glomerular inflammation, we next used a model of in situ immune complex-mediated glomerulonephritis, induced by anti-mouse glomerular basement membrane antibody (anti-GBM Ab).2Kuligowski M.P. Kitching A.R. Hickey M.J. Leukocyte recruitment to the inflamed glomerulus: a critical role for platelet-derived P-selectin in the absence of rolling.J Immunol. 2006; 176: 6991-6999Google Scholar, 3Devi S. Kuligowski M.P. Kwan R.Y. et al.Platelet recruitment to the inflamed glomerulus occurs via an alphaIIbbeta3/GPVI-dependent pathway.Am J Pathol. 2010; 177: 1131-1142Google Scholar, 4Devi S. Li A. Westhorpe C.L. et al.Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus.Nat Med. 2013; 19: 107-112Google Scholar Platelet dynamics in control, normal sheep globulin (NSG)-treated mice were similar to those in untreated mice (Figure 2a, Supplementary Movie S3). After anti-GBM Ab, a significant increase in the number of adherent platelets occurred within 30 minutes (Figure 2a, Supplementary Movie S3), with both the number of platelet interactions with neutrophils and the proportion of the interactions that involved neutrophils being significantly increased (Figure 2b and c). More striking changes were observed when assessing platelet dwell time. Twenty minutes after anti-GBM Ab administration, platelets interacting with neutrophils displayed a significantly elevated dwell time relative to those in NSG-treated mice (Figure 2d and e, Supplementary Movie S3). In contrast, the mean duration of platelet interactions not involving neutrophils remained unaltered (Figure 2f), suggesting a key role for neutrophils in increasing platelet retention in acutely inflamed glomeruli. Consistent with this, neutrophil depletion significantly reduced the number of platelets retained in glomerular capillaries for >10 seconds, although a small number of prolonged interactions remained (Supplementary Figure S1B and C). We also investigated intraglomerular platelet interactions with patrolling monocytes, using Cx3cr1gfp/+ mice to enable detection of monocytes. Platelets underwent constitutive interactions with patrolling monocytes (Supplementary Figure S2A, Supplementary Movie S4), although at lower frequency compared with that of neutrophils. While the number of platelets interacting with monocytes was similar after anti-GBM Ab injection (Supplementary Figure S2A), the mean dwell time of these interactions was significantly elevated during inflammation (Supplementary Figure S2B). Moreover, the number of platelets interacting with monocytes for at least 10 seconds underwent a small but significant increase (Supplementary Figure S2C), offering a potential explanation for the previous finding that neutrophil depletion did not remove all prolonged platelet interactions (Supplementary Figure S1C). These data indicate that the prolongation of platelet retention in inflamed glomeruli is dependent on alterations of interactions with both neutrophils and monocytes. Given that P-selectin facilitates neutrophil-platelet interactions in other settings, we next investigated the role of P-selectin in intraglomerular platelet-neutrophil interactions. Inhibition of P-selectin did not affect the number of platelets adhering in glomerular capillaries (Figure 3a), or the percentage of platelets interacting with neutrophils after anti-GBM Ab administration (Figure 3b). However, P-selectin inhibition did attenuate the increase in dwell time of platelets interacting with neutrophils (Figure 3c), while not impacting on the dwell time of interactions with structures other than neutrophils (Figure 3d). We previously demonstrated that glomerular injury in this model is mediated by both platelets and neutrophils.2Kuligowski M.P. Kitching A.R. Hickey M.J. Leukocyte recruitment to the inflamed glomerulus: a critical role for platelet-derived P-selectin in the absence of rolling.J Immunol. 2006; 176: 6991-6999Google Scholar, 4Devi S. Li A. Westhorpe C.L. et al.Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus.Nat Med. 2013; 19: 107-112Google Scholar Therefore, we next examined whether prolonged platelet-neutrophil interactions were associated with induction of the proinflammatory actions of neutrophils, using platelet depletion to remove the effects of platelets. After platelet depletion, the number of adherent neutrophils following anti-GBM Ab was reduced by ∼50% due solely to a reduction in the number of crawling cells (Figure 4a and b ), while the dwell time of the remaining neutrophils was unaffected (Figure 4c). In contrast, platelet depletion did not alter the number or dwell time of adherent monocytes (Supplementary Figure S2D and E). We next examined whether removal of platelets affected the capacity of intraglomerular neutrophils to generate ROS, using dihydroethidium (DHE) to detect ROS-generating cells. Platelet depletion almost completely inhibited neutrophil ROS production (Figure 4a, Supplementary Movies S5 and S6). This effect was not simply a reflection of the reduction in the number of adherent neutrophils following platelet depletion, as the proportion of the remaining adherent cells that were DHE+ was also significantly reduced (Figure 4d). We next investigated the behavior of intraglomerular neutrophils following P-selectin inhibition. P-selectin blockade resulted in a reduction in the number of adherent neutrophils, without altering the dwell time of the remaining adherent neutrophils, and also reduced neutrophil ROS generation (Figure 4e–g). These results indicate a role for platelets in promoting neutrophil adhesion and activation in the acutely inflamed glomerulus via a mechanism dependent at least in part on prolonged P-selectin–mediated platelet-neutrophil interactions. We next investigated the roles of platelet-derived mediators that can promote neutrophil adhesion and activation, focusing on the CXC chemokine ligand 7 (CXCL7) and CXCL4 and the inflammatory lipid mediator, platelet-activating factor (PAF). CXCL7 inhibition did not alter the number or dwell time of adherent neutrophils, but it did induce a significant reduction in the number of crawling neutrophils (Figure 5a and b ). The number of neutrophils positive for ROS production was also significantly reduced by CXCL7 inhibition, while the abundance of DHE-ve neutrophils was unchanged (Figure 5c and d), suggesting a role for CXCL7 in promoting neutrophil activation in the glomerulus. In contrast, CXCL4 inhibition did not alter neutrophil adhesion, dwell time, or ROS production (Supplementary Figure S3A–D). The PAF receptor antagonist WEB 2086 reduced the number of adherent neutrophils in inflamed glomeruli (Figure 5e), although this intervention did not affect neutrophil dwell time (Figure 5f). However, in contrast to CXCL7 inhibition, WEB 2086 reduced adhesion of both DHE+ and DHE-ve neutrophils (Figure 5g), without altering the proportion of adherent cells that were DHE+ (Figure 5h). Thromboxane A2 (TxA2) and adenosine diphosphate (ADP) released from activated platelets have been shown to promote neutrophil activation in platelet-neutrophil aggregates.42Carestia A. Kaufman T. Rivadeneyra L. et al.Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets.J Leukoc Biol. 2016; 99: 153-162Google Scholar, 43Caudrillier A. Kessenbrock K. Gilliss B.M. et al.Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury.J Clin Invest. 2012; 122: 2661-2671Google Scholar, 44Maugeri N. Evangelista V. Celardo A. et al.Polymorphonuclear leukocyte-platelet interaction: role of P-selectin in thromboxane B2 and leukotriene C4 cooperative synthesis.Thromb Haemost. 1994; 72: 450-456Scopus (111) Google Scholar, 45Rossaint J. Herter J.M. Van Aken H. et al.Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation.Blood. 2014; 123: 2573-2584Google Scholar Therefore, we also examined the roles of these mediators in the glomerulus. Neither the P2Y12 receptor antagonist ticagrelor, nor inhibition of the TxA2 pathway via the thromboxane receptor (TP) antagonist SQ-29548, affected the number or dwell time of adherent neutrophils following anti-GBM Ab administration (Figure 6a and b ). Similarly, ticagrelor had no effect on the number and duration of platelet interactions in the glomerulus (Supplementary Figure S4A–D). SQ-29548 did not reduce but increased platelet-neutrophil interactions and caused intermittent increases in interaction duration (Supplementary Figure S4E–H). In contrast, inhibition of these receptor pathways significantly reduced the percentage of DHE+ neutrophils (Figure 6c), indicating roles for the TxA2/TP receptor and ADP/P2Y12 pathways in neutrophil activation, but not recruitment, in the acutely inflamed glomerulus. Together, these data indicate that platelet-derived mediators have differing roles in neutrophil recruitment and activation in glomeruli. Finally we examined the effects of these antiplatelet therapies on anti-GBM Ab-induced glomerular dysfunction, via assessment of albuminuria-urinary creatinine ratio. Treatment with ticagrelor, SQ-29548, anti-CXCL7, or WEB 2086 did not alter anti-GBM-Ab–induced glomerular dysfunction as assessed via this readout (Figure 7). While we have shown that platelets are retained in acutely inflamed glomeruli, the adhesive substrate supporting this response was not characterized.2Kuligowski M.P. Kitching A.R. Hickey M.J. Leukocyte recruitment to the inflamed glomerulus: a critical role for platelet-derived P-selectin in the absence of rolling.J Immunol. 2006; 176: 6991-6999Google Scholar, 3Devi S. Kuligowski M.P. Kwan R.Y. et al.Platelet recruitment to the inflamed glomerulus occurs via an alphaIIbbeta3/GPVI-dependent pathway.Am J Pathol. 2010; 177: 1131-1142Google Scholar Capitalizing on the capacity of SD-IVM to detect short-lived interactions, here we observed that platelets interact with a range of substrates in the glomerulus, including endothelial cells, neutrophils, and monocytes. Given the abundance of platelets in the circulation and our recent findings that both neutrophils and monocytes undergo spontaneous adhesion and migration in glomerular capillaries,4Devi S. Li A. Westhorpe C.L. et al.Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus.Nat Med. 2013; 19: 107-112Google Scholar, 5Finsterbusch M. Hall P. Li A. et al.Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus.Proc Natl Acad Sci U S A. 2016; 113: E5172-E5181Google Scholar these findings were anticipated. However, the changes induced by acute inflammation were unexpected in that despite the inflammatory stimulus being targeted to" @default.
• W2902399144 created "2018-12-11" @default.
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• W2902399144 date "2019-02-01" @default.
• W2902399144 modified "2023-10-18" @default.
• W2902399144 title "Platelet retention in inflamed glomeruli occurs via selective prolongation of interactions with immune cells" @default.
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