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Erythropoiesis and Splenomegaly Innate Immune Activation during Salmonella Infection Initiates Extramedullary Erythropoiesis and Splenomegaly This information is current as Amy Jackson, Minelva R. Nanton, Hope O'Donnell, Adovi of September 27, 2021. D. Akue and Stephen J. McSorley J Immunol published online 15 October 2010 http://www.jimmunol.org/content/early/2010/10/15/jimmun ol.1001198 Downloaded from Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on September 27, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 15, 2010, doi:10.4049/jimmunol.1001198 The Journal of Immunology Innate Immune Activation during Salmonella Infection Initiates Extramedullary Erythropoiesis and Splenomegaly Amy Jackson, Minelva R. Nanton, Hope O’Donnell, Adovi D. Akue, and Stephen J. McSorley Systemic Salmonella infection commonly induces prolonged splenomegaly in murine or human hosts. Although this increase in splenic cellularity is often assumed to be due to the recruitment and expansion of leukocytes, the actual cause of splenomegaly remains unclear. We monitored spleen cell populations during Salmonella infection and found that the most prominent increase is found in the erythroid compartment. At the peak of infection, the majority of spleen cells are immature CD712Ter119+ retic- ulocytes, indicating that massive erythropoiesis occurs in response to Salmonella infection. Indeed, this increase in RBC precur- sors corresponded with marked elevation of serum erythropoietin (EPO). Furthermore, the increase in RBC precursors and EPO production required innate immune signaling mediated by Myd88/TRIF. Neutralization of EPO substantially reduced the imma- Downloaded from ture RBC population in the spleen and allowed a modest increase in host control of infection. These data indicate that early innate immunity to Salmonella initiates marked splenic erythropoiesis and may hinder bacterial clearance. The Journal of Immunology, 2010, 185: 000–000. almonella infections are typically transmitted by contami- CD4 T cells are activated rapidly postinfection, it takes several nated food or water and can cause a spectrum of clinical weeks to develop Salmonella-specific Th1 cells that are capable of http://www.jimmunol.org/ S manifestations, ranging from uncomplicated local gastro- producing large amounts of IFN-g and controlling intracellular enteritis to typhoid (1, 2). The outcome of Salmonella infection bacterial replication (11, 12). In the absence of Th1 cells or IFN-g, depends on the particular bacterial serovar and both the genetic the infected host is unable to regulate bacterial growth and even- susceptibility and immune competence of the infected host (1, 2). tually succumbs to infection (13, 14). The increasing incidence of Salmonella antibiotic resistance and During systemic infection, Salmonella spp. replicate extensively the limited potential for the development of new antibiotics (3–5) within phagocyte populations of the GALTs, spleen, liver, and necessitate the generation of new Salmonella vaccines. However, bone marrow (15, 16). The early innate immune response to in- for this goal to be realized, a greater understanding of bacteria– fection invokes chemokine-dependent recruitment of neutrophils host interactions and immunity to infection is required. and monocytes to the infected site, where they can be activated to by guest on September 27, 2021 Salmonella spp. are facultative intracellular bacteria that are produce inducible NO synthase and kill bacteria (16, 17). How- able to survive macrophage phagocytosis and replicate within ever, recruitment of phagocytes can also be counterproductive, a modified endosome, called the Salmonella-containing vacuole because these newly recruited phagocytes provide a rich source (6, 7). Salmonella-containing vacuole formation is regulated by of new cells for additional infection. Indeed, prior depletion of multiple Salmonella virulence genes, which allow adaptation of phagocytes actually increases host resistance to Salmonella in- the macrophage intracellular environment for optimal bacterial fection (18). In addition to recruitment of phagocytes, Salmonella growth (7). Infected phagocytes therefore require an activation infection also induces marked activation and expansion of CD4 signal provided by IFN-g to initiate bactericidal processes that and CD8 T cells (19–21), the majority of which appear to be overcome phagosome modifications and eliminate the infecting Salmonella-specific and eventually control bacterial replication bacteria (8). During the early stages of Salmonella infection, IFN-g (22). Thus, a hallmark of Salmonella infection is increased cellularity is provided by cells of the innate immune system, such as NK cells, of the spleen, owing in part to recruitment and expansion of phago- neutrophils, and macrophages, thus allowing the host to restrain cyte and lymphocyte populations responding to infection. Although initial bacterial growth while a Salmonella-specific adaptive im- the splenomegaly accompanying Salmonella infection is sometimes mune response develops (9, 10). Although Salmonella-specific attributed to this increase in splenic leukocytes, the contribution of other cell populations is not always carefully examined. Center for Infectious Diseases and Microbiology Translational Research and Division The expansion and differentiation of erythroid cells usually of Gastroenterology, Hepatology and Nutrition, Department of Medicine, McGuire occurs in the bone marrow and is tightly regulated by the pro- Translational Research Facility, University of Minnesota Medical School, Minneap- duction of the hormone erythropoietin (EPO). Erythroid progen- olis, MN 55455 itor cells respond to EPO and progress through a series of well- Received for publication April 13, 2010. Accepted for publication September 9, 2010. characterized differentiation stages before extruding nuclei and forming mature circulating erythrocytes (23, 24). This process of This work was supported by Grants AI055743, AI56172, and AI076278 from the National Institutes of Health. erythroid differentiation is normally regulated so that sufficient Address correspondence and reprint requests to Stephen J. McSorley, University of erythrocytes are produced in the bone marrow. However, under Minnesota Medical Center, Center for Infectious Diseases and Microbiology Trans- conditions of stress, erythroid differentiation can become dys- lational Research, TRF, 2001 6th Street SE, Minneapolis, MN 55455. E-mail address: regulated, and a large increase in erythrocytes can be initiated in [email protected] the spleen (25), termed “extramedullary erythropoiesis”. Abbreviations used in this paper: EPO, erythropoietin; WT, wild type. Erythropoiesis can also be substantially altered during infec- Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 tion with microbial pathogens. For example, infection with Friend www.jimmunol.org/cgi/doi/10.4049/jimmunol.1001198 2 ERYTHROPOIESIS DURING SALMONELLA INFECTION spleen focus-forming virus initiates erythroid hyperplasia in the science; BD Biosciences). After staining, cells were fixed using parafor- absence of EPO (26), and studies published decades earlier clearly maldehyde and examined by flow cytometry using a FACS Canto. All flow demonstrate that injection of bacterial endotoxin can reduce bone data were analyzed using FlowJo software (Tree Star). marrow, but increase splenic erythropoiesis (27–29). A more re- EPO measurement cent study reported that Salmonella infection can cause erythroid depletion of the bone marrow and a corresponding increase in Blood was collected by retro-orbital bleeding of anesthetized, infected, and uninfected mice and incubated at room temperature for 2 h. Each sample splenic erythropoiesis (30). However, the initiation of splenic was centrifuged in a bench-top centrifuge to pellet the RBCs, and serum was erythropoiesis during Salmonella infection has received relatively collected and stored at 220˚C. EPO concentrations in serum samples were little attention. measured using the Quantikine Mouse/Rat Epo Immunoasssay (R&D In this study, we examined the process of splenomegaly during Systems, Minneapolis, MN) following the recommended protocol. murine Salmonella infection. Our data show that a massive in- In vivo blockade of EPO crease in immature erythroid reticulocytes accounts for the greatest single change in splenic cell populations following Salmonella Salmonella-infected mice were injected i.v. with 250 mg monoclonal rat anti-mouse EPO or rat IgG2a isotype control (R&D Systems) in PBS, infection. Expansion of this erythroid population was initiated by 2 and 4 d postinfection. Blood was collected by retro-orbital bleeding of a marked increase in EPO production, which required recognition anesthetized mice on days 4 and 7 postinfection,
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