RESUMEN
Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype that potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and have implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
Asunto(s)
Enfermedad Injerto contra Huésped , Microglía , Enfermedades Neuroinflamatorias , Receptor Cannabinoide CB2 , Animales , Ratones , Aloinjertos , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Ratones Noqueados , Microglía/metabolismo , Microglía/inmunología , Microglía/patología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/metabolismo , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Receptor Cannabinoide CB2/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , MasculinoRESUMEN
Paneth cell metaplasia (PCM) typically arises in pre-existing gastrointestinal (GI) diseases; however, the mechanistic pathway that induces metaplasia and whether PCM is initiated exclusively by disorders intrinsic to the GI tract is not well known. Here, we describe the development of PCM in a murine model of chronic myelogenous leukemia (CML) that is driven by an inducible bcr-abl oncogene. Mechanistically, CML induces a proinflammatory state within the GI tract that results in the production of epithelial-derived IL-33. The binding of IL-33 to the decoy receptor ST2 leads to IL-9 production by type 2 innate lymphoid cells (ILC2) which is directly responsible for the induction of PCM in the colon and tissue remodeling in the small intestines, characterized by goblet and tuft cell hyperplasia along with expansion of mucosal mast cells. Thus, we demonstrate that an extra-intestinal disease can trigger an ILC2/IL-9 immune circuit, which induces PCM and regulates epithelial cell fate decisions in the GI tract.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Células de Paneth , Animales , Ratones , Interleucina-9/genética , Inmunidad Innata , Interleucina-33/genética , Linfocitos , Intestino Delgado , MetaplasiaRESUMEN
Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
RESUMEN
Acute cholangitis is a biliary tract infection secondary to the obstruction, which causes biliary stasis and bacterial overgrowth. Typically, it presents with the Charcot triad of right upper quadrant abdominal pain, jaundice, and fever. Most acute cholangitis cases are secondary to choledocholithiasis. There are rare cases resulting from pancreatic neoplasm. We report the case of a 43-year-old Caucasian male who was found unresponsive at home with hypotension, anemia, and severe jaundice. Initial imaging studies were notable for a periampullary mass lesion causing intrahepatic biliary ductal dilation. Endoscopic retrograde cholangiopancreatography (ERCP) revealed an actively oozing periampullary fungating mass. In this case, acute cholangitis and hemorrhagic shock secondary to bleeding periampullary lesions are atypical. This case presents an effective treatment plan for this condition.
RESUMEN
Rho GTPases such as Rho, Rac, and Cdc42 are important regulators of the cortical cytoskeleton in processes including cell division, locomotion, and repair. In these processes, Rho GTPases assume characteristic patterns wherein the active GTPases occupy mutually exclusive "zones" in the cell cortex. During cell wound repair, for example, a Rho zone encircles the wound edge and is in turn encircled by a Cdc42 zone. Here we evaluated the contributions of cross-talk between Rho and Cdc42 to the patterning of their respective zones in wounded Xenopus oocytes using experimental manipulations in combination with mathematical modeling. The results show that the position of the Cdc42 zone relative to the Rho zone and relative to the wound edge is controlled by the level of Rho activity. In contrast, the outer boundary of the Rho zone is limited by the level of Cdc42 activity. Models based on positive feedback within zones and negative feedback from Rho to the GEF-GAP Abr to Cdc42 capture some, but not all, of the observed behaviors. We conclude that GTPase zone positioning is controlled at the level of Rho activity and we speculate that the Cdc42 zone or something associated with it limits the spread of Rho activity.
Asunto(s)
Proteínas de Unión al GTP Monoméricas/metabolismo , Oocitos/fisiología , Transducción de Señal , Proteínas de Xenopus/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Animales , Citoesqueleto , Modelos Biológicos , Oocitos/metabolismo , Xenopus laevis/metabolismo , Xenopus laevis/fisiologíaRESUMEN
Early innate education of hematopoietic progenitors within the bone marrow (BM) stably primes them for either trained immunity or instead immunoregulatory functions. We herein demonstrate that in vivo or in vitro activation within the BM via Toll-like receptor-9 generates a population of plasmacytoid dendritic cell (pDC) precursors (CpG-pre-pDCs) that, unlike pDC precursors isolated from PBS-incubated BM (PBS-pre-pDCs), are endowed with the capacity to halt progression of ongoing experimental autoimmune encephalomyelitis. CpG activation enhances the selective migration of pDC precursors to the inflamed spinal cord, induces their immediate production of TGF-ß, and after migration, of enhanced levels of IL-27. CpG-pre-pDC derived TGF-ß and IL-27 ensure protection at early and late phases of the disease, respectively. Spinal cords of CpG-pre-pDC-protected recipient mice display enhanced percentages of host-derived pDCs expressing TGF-ß as well as an accumulation of IL-10 producing B cells and of CD11c+ CD11b+ dendritic cells. These results reveal that pDC precursors are conferred stable therapeutic properties by early innate activation within the BM. They further extend to the pDC lineage promising perspectives for cell therapy of autoimmune diseases with innate activated hematopoietic precursor cells.
Asunto(s)
Células de la Médula Ósea/citología , Células Dendríticas/citología , Esclerosis Múltiple/patología , Médula Espinal/citología , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Interleucina-27/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Esclerosis Múltiple/inmunología , Médula Espinal/inmunología , Médula Espinal/metabolismo , Receptor Toll-Like 9 , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Animal cell cytokinesis results from patterned activation of the small GTPase Rho, which directs assembly of actomyosin in the equatorial cortex. Cytokinesis is restricted to a portion of the cell cycle following anaphase onset in which the cortex is responsive to signals from the spindle. We show that shortly after anaphase onset oocytes and embryonic cells of frogs and echinoderms exhibit cortical waves of Rho activity and F-actin polymerization. The waves are modulated by cyclin-dependent kinase 1 (Cdk1) activity and require the Rho GEF (guanine nucleotide exchange factor), Ect2. Surprisingly, during wave propagation, although Rho activity elicits F-actin assembly, F-actin subsequently inactivates Rho. Experimental and modelling results show that waves represent excitable dynamics of a reaction-diffusion system with Rho as the activator and F-actin the inhibitor. We propose that cortical excitability explains fundamental features of cytokinesis including its cell cycle regulation.
Asunto(s)
Actinas/metabolismo , Citocinesis , Transducción de Señal , Proteínas de Unión al GTP rho/metabolismo , Anafase , Animales , Proteína Quinasa CDC2/metabolismo , Centrosoma/metabolismo , Citoplasma/metabolismo , Embrión no Mamífero/citología , Embrión no Mamífero/metabolismo , Femenino , Factores de Intercambio de Guanina Nucleótido/metabolismo , Cinética , Microscopía Confocal , Microtúbulos/metabolismo , Oocitos/metabolismo , Polimerizacion , Huso Acromático/metabolismo , Estrellas de Mar , Imagen de Lapso de Tiempo/métodos , Xenopus laevisRESUMEN
Cell repair is attracting increasing attention due to its conservation, its importance to health, and its utility as a model for cell signaling and cell polarization. However, some of the most fundamental questions concerning cell repair have yet to be answered. Here we consider three such questions: (1) How are wound holes stopped? (2) How is cell regeneration achieved after wounding? (3) How is calcium inrush linked to wound stoppage and cell regeneration?