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Exhaustion Innate Immune Suppression Rather Than The Journal of Immunology Acute-Phase Deaths from Murine Polymicrobial Sepsis Are Characterized by Innate Immune Suppression Rather Than Exhaustion Evan L. Chiswick,* Juan R. Mella,† John Bernardo,‡ and Daniel G. Remick* Sepsis, a leading cause of death in the United States, has poorly understood mechanisms of mortality. To address this, our model of cecal ligation and puncture (CLP) induced sepsis stratifies mice as predicted to Live (Live-P) or Die (Die-P) based on plasma IL-6. Six hours post-CLP, both Live-P and Die-P groups have equivalent peritoneal bacterial colony forming units and recruitment of phagocytes. By 24 h, however, Die-P mice have increased bacterial burden, despite increased neutrophil recruitment, suggesting Die-P phagocytes have impaired bacterial killing. Peritoneal cells were used to study multiple bactericidal processes: bacterial killing, reactive oxygen species (ROS) generation, and phagocytosis. Total phagocytosis and intraphagosomal processes were deter- mined with triple-labeled Escherichia coli, covalently labeled with ROS- and pH-sensitive probes, and an ROS/pH-insensitive probe for normalization. Although similar proportions of Live-P and Die-P phagocytes responded to exogenous stimuli, Die-P phagocytes showed marked deficits in all parameters measured, thus suggesting immunosuppression rather than exhaustion. This contradicts the prevailing sepsis paradigm that acute-phase sepsis deaths (<5 d) result from excessive inflammation, whereas chronic-phase deaths (>5 d) are characterized by insufficient inflammation and immunosuppression. These data suggest that suppression of cellular innate immunity in sepsis occurs within the first 6 h. The Journal of Immunology, 2015, 195: 3793–3802. epsis is an immune-mediated immune disorder costing so- teases (6). Similarly, macrophages and inflammatory monocytes ciety approximately $24 billion annually (1), and claiming phagocytize microbes and process them in a manner similar to S .200,000 lives per year (2). Despite causing a similar endosomal cargo, ultimately fusing with lysosomes and digesting number of lives lost as cancer, there are few treatment options the bacteria via pH-sensitive proteases (7). As the first responders available. Currently, patients receive aggressive treatment that in an immune response, they are central to the initiation of sepsis. includes fluid resuscitation, vasopressors, and broad spectrum Cecal ligation and puncture (CLP) induced peritonitis in antibiotics (3). Despite these interventions, postmortem studies outbred mice produces a spectrum of inflammation ranging from revealed the majority of patients still had infectious foci present a rampant inflammatory response that is thought to become (4), thus suggesting a deficit in bacterial clearance. dysregulated, leading to immune paralysis, bacterial overgrowth, Neutrophils and macrophages comprise the phagocytic arm of and death (8). At the other end of the spectrum is a tightly theinnateimmunesystemlargely responsible for eradicating regulated response that clears pathogens without inducing host a bacterial infection. Following infection, tissue macrophages damage. Studies have shown that altering leukocyte recruitment engage the pathogen and secrete distress factors to recruit (9) or enhancing leukocyte function results in decreased bac- neutrophils and inflammatory monocytes. Neutrophils help to terial burden (10), increased organ perfusion (11, 12), and ul- neutralize the infection by secreting neutrophil extracellular timately increased survival. However, the majority of these traps (NETs) (5) and/or by phagocytizing microbes and expos- studies compare sham-operated animals to CLP operated. Al- ing them to reactive oxygen species (ROS) and cationic pro- though this approach helps define the host response to sepsis, it may be less appropriate for delineating the mechanisms of sepsis *Department of Pathology and Laboratory Medicine, Boston University School of mortality. Medicine, Boston, MA 02118; †Department of Surgery, Boston University Medical Center, Boston, MA 02118; and ‡Division of Pulmonary, Allergy, and Critical Care Previousstudieshaveshownthatwithin6hofCLPinmice, Medicine, Boston University Medical Center, Boston, MA 02118 circulating biomarkers can be used to accurately predict mortality Received for publication April 14, 2015. Accepted for publication August 3, 2015. during the acute phase of sepsis (13). This powerful capability This work was supported in part by National Institutes of Health Grants enables stratified interventions to assess efficacy (14, 15), and it T32AI007309, T32HL007501, R01GM97320, T32GM86308, and R21AI112887. provides a window of time in which to observe the detrimental E.L.C. performed experiments and analyzed data; J.R.M. cultured bacteria from divergence between survivors and nonsurvivors. This approach peritoneal cavity and prepared data; J.B. provided equipment, reagents, technical expertise, and intellectual support; and E.L.C. and D.G.R. conceived the study and revealed that similar peritoneal bacterial CFUs and phagocyte wrote the manuscript. recruitment occurs 6 h after CLP. However by 24 h, nonsurvivors Address correspondence and reprint requests to Dr. Daniel G. Remick, Department of recruited significantly more phagocytes, yet they also showed Pathology and Laboratory Medicine, Boston University School of Medicine, 670 Albany Street, Room 407, Boston, MA 02118. E-mail address: [email protected] significantly increased bacterial burden (16). We hypothesized that phagocytes from nonsurvivors were The online version of this article contains supplemental material. impaired in their bacterial killing capacity. If the cell function was Abbreviations used in this article: CLP, cecal ligation and puncture; DHR-123, dihy- drorhodamine 1,2,3; Fsc, forward light scatter; MDSC, myeloid-derived suppressor reduced, the host attempted to correct by increasing the numbers cell; NET, neutrophil extracellular trap; NOX, NADPH oxidase; OpH–E. coli, opson- of phagocytic cells. The current study examined whether reduced ized pHrodo–labeled E. coli; ROS, reactive oxygen species; TB, trypan blue. cellular killing of bacteria occurs in mice predicted to die and Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 define the mechanisms of this impairment. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500874 3794 ACUTE-PHASE SEPSIS DEATHS FROM IMMUNOSUPPRESSION Materials and Methods Basal ROS and ROS burst kinetics Animals Peritoneal cells were added to white-opaque microplate wells in duplicate at 3 6 m Female ICR (CD-1) mice (Harlan-Sprague Dawley, South Easton, MA) 24– a concentration of 4 10 /ml. Luminol was present at 20 M. Cells were 28 g were used for all studies. Mice were received and acclimated to our placed in a temperature-controlled fluorescent plate reader (Tecan Infinite housing room for at least 96 h prior to surgery and cared for as described m1000) and warmed to 37˚C for 5 min. Stimulus was then added (100 nM PMA or 20:1 bacteria:cell), and chemiluminescence was measured every previously (16). The experiments were approved by the Boston University ∼ Animal Care and Use Committee. 10 s (0.5-s integration time) followed by mechanical shaking. 3 Sepsis model 3 -Labeled bacteria preparation Labeling was performed as published previously (23). Briefly, 2 3 1010/ml Cecal ligation and puncture was performed as first described (17) with heat-killed (80˚C at 1 h) HB101 E. coli were sequentially labeled with minor modifications (16, 18). Approximately two-thirds the length of the 500 mM dihydrodichlorofluorescein-succinimidyl ester to detect ROS, cecum from the distal tip was ligated and then double punctured longi- 50 mM pHrodo-SE to detect pH changes, and 159 mM Alexa Fluor-350-SE tudinally with 16-gauge needle. Mice were resuscitated with 1 ml saline to calibrate DCF/pHrodo fluorescence (Life Technologies). Labeling was (37˚C) with buprenorphine (0.05 mg/kg) for pain management (one in- performed in PBS (pH 9), degassed, and purged with N to minimize auto jection every 12 h for 2 d). Antibiotics (25mg/kg imipenem) were ad- 2 oxidation of DCF. Bacteria (∼1.5 3 1010/ml) were opsonized with 1/10th ministered 2 h post-CLP and then once every 12 h for 5 d. volume of normal mouse plasma (heparinized) and anti–E. coli Abs m Sampling (50 g/ml) (Life Technologies). The use of particles covalently labeled with multiple fluorescent indicators/substrates provides temporal, spatial, Blood sampling was performed initially at 6 and 24 h to generate IL-6 and calibrated information for phagocytosis and phagosomal events that receiver operator characteristic curves and discrimination levels for pre- are not readily available with most cell permeable dyes. These approaches dicting survival. Blood (20 ml) was collected by facial vein puncture and have been validated in previous publications (24, 25). diluted 1/10 in PBS containing 3.38 mM EDTA tripotassium salt. Blood was centrifuged for 5 min at 1000 3 g, and the plasma was frozen at 220˚C. Phagocytosis and phagosomal ROS/acidification of For mice that were sacrificed, blood was collected from the retro-orbital 33-labeled bacteria venous plexus under anesthesia (ketamine/xylazine), followed by eutha- Peritoneal cells were loaded into polypropylene cryovials at 4 3 106/ml. nasia via cervical dislocation. Plasma collected at 6 and/or 24 h was an- ∼ alyzed for IL-6 concentrations by ELISA as described previously (19). While on ice, 150 bacteria/cell were added to cells. Tubes were trans- ferred to a
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