Person: Pittet, Mikael
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Pittet
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Mikael
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Pittet, Mikael
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Publication Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging(Nature Publishing Group, 2017) Cuccarese, Michael F.; Dubach, J. Matthew; Pfirschke, Christina; Engblom, Camilla; Garris, Christopher; Miller, Miles; Pittet, Mikael; Weissleder, RalphInvolvement of the immune system in tumour progression is at the forefront of cancer research. Analysis of the tumour immune microenvironment has yielded a wealth of information on tumour biology, and alterations in some immune subtypes, such as tumour-associated macrophages (TAM), can be strong prognostic indicators. Here, we use optical tissue clearing and a TAM-targeting injectable fluorescent nanoparticle (NP) to examine three-dimensional TAM composition, tumour-to-tumour heterogeneity, response to colony-stimulating factor 1 receptor (CSF-1R) blockade and nanoparticle-based drug delivery in murine pulmonary carcinoma. The method allows for rapid tumour volume assessment and spatial information on TAM infiltration at the cellular level in entire lungs. This method reveals that TAM density was heterogeneous across tumours in the same animal, overall TAM density is different among separate pulmonary tumour models, nanotherapeutic drug delivery correlated with TAM heterogeneity, and successful response to CSF-1R blockade is characterized by enhanced TAM penetration throughout and within tumours.Publication Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system(2017) Jijon, Humberto B.; Suarez-Lopez, Lucia; Diaz, Oscar E.; Das, Srustidhar; De Calisto, Jaime; Yaffe, Michael; Pittet, Mikael; Mora, J. Rodrigo; Belkaid, Yasmine; Xavier, Ramnik; Villablanca, Eduardo J.Retinoic acid (RA), a dietary vitamin A metabolite, is crucial in maintaining intestinal homeostasis. RA acts on intestinal leukocytes to modulate their lineage commitment and function. Although the role of RA has been characterized in immune cells, whether intestinal epithelial cells (IECs) rely on RA signaling to exert their immune-regulatory function has not been examined. Here we demonstrate that lack of retinoic acid receptor alpha (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack or RARα resulted in increased KLF4+ goblet cell precursors in the distal bowel, whereas RA treatment inhibited klf4 expression and goblet cell differentiation in zebrafish. These changes in secretory cells are associated with increased reg3g, reduced luminal bacterial detection and an underdeveloped intestinal immune system, as evidenced by an almost complete absence of lymphoid follicles and gut resident mononuclear phagocytes. This underdeveloped intestinal immune system shows a decreased ability to clear infection with Citrobacter rodentium. Collectively, our findings indicate that epithelial cell-intrinsic RARα signaling is critical to the global development of the intestinal immune system.Publication Longitudinal confocal microscopy imaging of solid tumor destruction following adoptive T cell transfer(Landes Bioscience, 2013) Schietinger, Andrea; Arina, Ainhoa; Liu, Rebecca B; Wells, Sam; Huang, Jianhua; Engels, Boris; Bindokas, Vytas; Bartkowiak, Todd; Lee, David; Herrmann, Andreas; Piston, David W; Pittet, Mikael; Lin, P Charles; Zal, Tomasz; Schreiber, HansA fluorescence-based, high-resolution imaging approach was used to visualize longitudinally the cellular events unfolding during T cell-mediated tumor destruction. The dynamic interplay of T cells, cancer cells, cancer antigen loss variants, and stromal cells—all color-coded in vivo—was analyzed in established, solid tumors that had developed behind windows implanted on the backs of mice. Events could be followed repeatedly within precisely the same tumor region—before, during and after adoptive T cell therapy—thereby enabling for the first time a longitudinal in vivo evaluation of protracted events, an analysis not possible with terminal imaging of surgically exposed tumors. T cell infiltration, stromal interactions, and vessel destruction, as well as the functional consequences thereof, including the elimination of cancer cells and cancer cell variants were studied. Minimal perivascular T cell infiltrates initiated vascular destruction inside the tumor mass eventually leading to macroscopic central tumor necrosis. Prolonged engagement of T cells with tumor antigen-crosspresenting stromal cells correlated with high IFNγ cytokine release and bystander elimination of antigen-negative cancer cells. The high-resolution, longitudinal, in vivo imaging approach described here will help to further a better mechanistic understanding of tumor eradication by T cells and other anti-cancer therapies.Publication Remote control of macrophage production by cancer(Landes Bioscience, 2013) Cortez-Retamozo, Virna; Engblom, Camilla; Pittet, MikaelThe communication between tumor and host cells involves signals that act across extended distances in the body. Recent evidence indicates that the hormone angiotensin II is overproduced by lung adenocarcinoma to remotely expand bone marrow-derived hematopoietic stem cells. This process amplifies the supply of tumor-associated macrophages, which promote disease progression.Publication Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata(American Society for Clinical Investigation, 2007) Swirski, Filip; Libby, Peter; Aikawa, Elena; Alcaide, Pilar; Luscinskas, Francis; Weissleder, Ralph; Pittet, MikaelMacrophage accumulation participates decisively in the development and exacerbation of atherosclerosis. Circulating monocytes, the precursors of macrophages, display heterogeneity in mice and humans, but their relative contribution to atherogenesis remains unknown. We report here that the Ly-6C(hi) monocyte subset increased dramatically in hypercholesterolemic apoE-deficient mice consuming a high-fat diet, with the number of Ly-6C(hi) cells doubling in the blood every month. Ly-6C(hi) monocytes adhered to activated endothelium, infiltrated lesions, and became lesional macrophages. Hypercholesterolemia-associated monocytosis (HAM) developed from increased survival, continued cell proliferation, and impaired Ly-6C(hi) to Ly-6C(lo) conversion and subsided upon statin-induced cholesterol reduction. Conversely, the number of Ly-6C(lo) cells remained unaffected. Thus, we believe that Ly-6C(hi) monocytes represent a newly recognized component of the inflammatory response in experimental atherosclerosis.Publication Tumor associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug(2015) Miller, Miles; Zheng, Yao-Rong; Gadde, Suresh; Pfirschke, Christina; Zope, Harshal; Engblom, Camilla; Kohler, Rainer; Iwamoto, Yoshiko; Yang, Katherine; Askevold, Bjorn; Kolishetti, Nagesh; Pittet, Mikael; Lippard, Stephen J.; Farokhzad, Omid; Weissleder, RalphTherapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behavior. Model TNPs comprised of a fluorescent platinum(IV) pro-drug and a clinically-tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumor associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload, and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA damaging Pt payload gradually releases to neighboring tumor cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials.Publication Renal Intercalated Cells Sense and Mediate Inflammation via the P2Y14 Receptor(Public Library of Science, 2015) Azroyan, Anie; Cortez-Retamozo, Virna; Bouley, Richard; Liberman, Rachel; Ruan, Ye Chun; Kiselev, Evgeny; Jacobson, Kenneth A.; Pittet, Mikael; Brown, Dennis; Breton, SylvieUncontrolled inflammation is one of the leading causes of kidney failure. Pro-inflammatory responses can occur in the absence of infection, a process called sterile inflammation. Here we show that the purinergic receptor P2Y14 (GPR105) is specifically and highly expressed in collecting duct intercalated cells (ICs) and mediates sterile inflammation in the kidney. P2Y14 is activated by UDP-glucose, a damage-associated molecular pattern molecule (DAMP) released by injured cells. We found that UDP-glucose increases pro-inflammatory chemokine expression in ICs as well as MDCK-C11 cells, and UDP-glucose activates the MEK1/2-ERK1/2 pathway in MDCK-C11 cells. These effects were prevented following inhibition of P2Y14 with the small molecule PPTN. Tail vein injection of mice with UDP-glucose induced the recruitment of neutrophils to the renal medulla. This study identifies ICs as novel sensors, mediators and effectors of inflammation in the kidney via P2Y14.Publication Myocardial Infarction Accelerates Atherosclerosis(Nature Publishing Group, 2012) Leuschner, Florian; Robbins, Clinton; Iwamoto, Yoshiko; Thompson, Brian; Carlson, Alicia L.; Heidt, Timo; Lasitschka, Felix; Etzrodt, Martin; Waterman, Peter; Waring, Michael T.; Chicoine, Adam T.; van der Laan, Anja M.; Niessen, Hans W.M.; Piek, Jan J.; Rubin, Barry B.; Butany, Jagdish; Katus, Hugo A.; Murphy, Sabina A.; Pittet, Mikael; Lin, Charles; Dutta, Partha; Courties, Gabriel; Wei, Ying; Gorbatov, Rostic; Majmudar, Maulik; Stone, James; Morrow, David; Sabatine, Marc; Vinegoni, Claudio; Moskowitz, Michael; Libby, Peter; Swirski, Filip; Weissleder, Ralph; Nahrendorf, MatthiasDuring progression of atherosclerosis, myeloid cells destabilize lipid-rich plaque in the arterial wall and cause its rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, apoE\(^{−/−}\) mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. When seeking the source of surplus monocytes in plaque, we found that myocardial infarction liberated hematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signaling. The progenitors then seeded the spleen yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.Publication Multi-Scale In Vivo Systems Analysis Reveals the Influence of Immune Cells on TNF-α-Induced Apoptosis in the Intestinal Epithelium(Public Library of Science, 2012) Lau, Ken; Cortez-Retamozo, Virna; Philips, Sarah R.; Pittet, Mikael; Lauffenburger, Douglas A.; Haigis, KevinAn intercellular communication network that controls intestinal homeostasis in animals treated acutely with the pro-inflammatory cytokine TNF-α is uncovered by multi-scale systems analysis.Publication Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis(The Rockefeller University Press, 2012) Leuschner, Florian; Rauch, Philipp J.; Ueno, Takuya; Gorbatov, Rostic; Marinelli, Brett; Lee, Won Woo; Dutta, Partha; Wei, Ying; Robbins, Clinton; Iwamoto, Yoshiko; Sena, Brena; Chudnovskiy, Aleksey; Panizzi, Peter; Higgins, John; Libby, Peter; Moskowitz, Michael; Pittet, Mikael; Swirski, Filip; Weissleder, Ralph; Nahrendorf, MatthiasIL-1b signaling augments continued splenic monocyte supply during acute inflammation.