Extracellular Superoxide Dismutase Inhibits Innate Immune Responses and Clearance of an Intracellular Bacterial Infection

Break, Timothy J.; Jun, Sujung; Indramohan, Mohanalaxmi; Carr, Karen D.; Sieve, Amy N.; Dory, Ladislav; Berg, Rance E.

doi:10.4049/jimmunol.1102341

Cited by 46 publications

(45 citation statements)

References 46 publications

(58 reference statements)

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“…A similar association has been demonstrated for the attenuated BCG strain and other mutants of virulent M. tuberculosis; failure to control intramacrophage ROS production leads to an increased production of pro-inflammatory cytokines (62)(63)(64)(65)(66). Conversely, restriction of host ROS via overexpression of host superoxide dismutase results in the suppression of pro-inflammatory cytokines and impaired clearance of Listeria monocytogenes (67). These studies indicate a conserved theme of ROS-dependent cell signaling in the generation of innate immune responses and provide conceptual evidence that bacterial antioxidant enzymes prevent this response by inhibiting redox-sensitive signaling.…”

Section: Discussionsupporting

confidence: 60%

Antioxidant Defenses of Francisella tularensis Modulate Macrophage Function and Production of Proinflammatory Cytokines

Rabadi

Sanchez

Varanat

et al. 2016

Journal of Biological Chemistry

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Francisella tularensis, the causative agent of a fatal human disease known as tularemia, has been used in the bioweapon programs of several countries in the past, and now it is considered a potential bioterror agent. Extreme infectivity and virulence of F. tularensis is due to its ability to evade immune detection and to suppress the host's innate immune responses. However, Francisella-encoded factors and mechanisms responsible for causing immune suppression are not completely understood. Macrophages and neutrophils generate reactive oxygen species (ROS)/reactive nitrogen species as a defense mechanism for the clearance of phagocytosed microorganisms. ROS serve a dual role; at high concentrations they act as microbicidal effector molecules that destroy intracellular pathogens, and at low concentrations they serve as secondary signaling messengers that regulate the expression of various inflammatory mediators. We hypothesized that the antioxidant defenses of F. tularensis maintain redox homeostasis in infected macrophages to prevent activation of redox-sensitive signaling components that ultimately result in suppression of pro-inflammatory cytokine production and macrophage microbicidal activity. We demonstrate that antioxidant enzymes of F. tularensis prevent the activation of redox-sensitive MAPK signaling components, NF-B signaling, and the production of pro-inflammatory cytokines by inhibiting the accumulation of ROS in infected macrophages. We also report that F. tularensis inhibits ROS-dependent autophagy to promote its intramacrophage survival. Collectively, this study reveals novel pathogenic mechanisms adopted by F. tularensis to modulate macrophage innate immune functions to create an environment permissive for its intracellular survival and growth.Francisella tularensis is a Gram-negative intracellular pathogen and the causative agent of a fatal human disease known as tularemia. F. tularensis is classified into four subspecies as follows: F. tularensis subspecies tularensis; F. tularensis subspecies holarctica; F. tularensis subspecies mediasiatica, and F. tularensis subspecies novicida. All classifications are based on virulence, genetics, and metabolic characteristics. F. tularensis subspecies tularensis (type A) is the most virulent of all four Francisella subspecies. About 70% of tularemia cases in North America are a result of type A Francisella with an infectivity dose of less than 10 colony-forming units (cfu) in humans (1). The live vaccine strain (LVS) 3 is a derivative of Russian S15 strain of F. tularensis subspecies holarctica (type B). F. tularensis LVS is not approved for mass vaccinations in the United States due to adverse reactions in vaccinated individuals (2). F. tularensis LVS is relatively avirulent in humans and therefore commonly used as a surrogate for the more virulent SchuS4 strain to study tularemia pathogenesis. F. tularensis subspecies mediasiatica and novicida are rarely associated with human tularemia and have been isolated in Asia and in North America and Australia, re...

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Section: Discussionsupporting

confidence: 60%

Antioxidant Defenses of Francisella tularensis Modulate Macrophage Function and Production of Proinflammatory Cytokines

Rabadi

Sanchez

Varanat

et al. 2016

Journal of Biological Chemistry

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“…As studies impressively demonstrated: superoxide is able to kill bacteria directly, especially when the virulence of the pathogen is dramatically attenuated (i.e. by superoxide dismutase deficiency) [46] [47]. Here in this study, the inhibition of specific glutamine-dependent pathways were one important constituent in the significant turnaround of the pyruvate-induced alterations in the immune parameters examined.…”

Section: Pyruvate Induced Effects: Is There An Impact By Adding a Glumentioning

confidence: 57%

Pyruvate-Dependent Changes in Neutrophil Amino- and Alpha-Keto Acid Profiles or Immunity: Which Mechanisms Are Involved?

Deller¹,

Mathioudakis²,

Engel³

et al. 2014

OJI

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High current findings indicate that a substitution with pyruvate can lead to significant alterations or even improvement in neutrophil immunonutrition. However, it is still unknown which intracellular pathways might be involved here. Hence, in this study, we investigated whether preincubation with an inhibitor of •NO-synthase (L-NAME), an •NO donor (SNAP), an analogue of taurine (beta-alanine), an inhibitor of ornithine-decarboxylase (DFMO) as well as a glutamine-analogue (DON), is able to alter the intragranulocytic metabolic response to pyruvate, here for example studied for neutrophil intracellular amino-and α-keto acid concentrations or important neutrophil immune functions [released myeloperoxidase (MPO), the formation of superoxide anions ( ) 2 − O and hydrogen peroxide (H 2 O 2 )]. In summary, the interesting first results presented here showed, that any damage of specific metabolic pathways or mechanisms, which seem directly or indirectly to be involved in relevant pyruvate dependent granulocytic nutrient content or specific cellular tasks, could lead to therapeutically desired, but also to unexpected or even fatal consequences for the affected cells. We therefore continue to believe that pyruvate, irrespective of which exact biochemical mechanisms were involved, in neutrophils may satisfy the substantial metabolic demands for a potent intracellular nutrient.

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“…We have previously shown that ecSOD enhances the recruitment of neutrophils to the liver in mice prior to and during L. monocytogenes infection (24). However, the mechanism by which ecSOD enhances neutrophil recruitment is not understood.…”

Section: Resultsmentioning

confidence: 99%

“…It was also demonstrated that ecSOD activity enhances neutrophil recruitment to the liver both prior to and during L. monocytogenes infection (24). This observation is counterintuitive, as ecSOD activity increases the susceptibility of mice to L. monocytogenes infection and neutrophils are known to protect against L. monocytogenes infection (25,26).…”

mentioning

confidence: 99%

Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver

et al. 2016

Self Cite

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Listeria monocytogenes is a Gram-positive intracellular pathogen that causes spontaneous abortion in pregnant women, as well as septicemia, meningitis, and gastroenteritis, primarily in immunocompromised individuals. Although L. monocytogenes can usually be effectively treated with antibiotics, there is still around a 25% mortality rate with individuals who develop clinical listeriosis. Neutrophils are innate immune cells required for the clearance of pathogenic organisms, including L. monocytogenes. The diverse roles of neutrophils during both infectious and noninfectious inflammation have recently gained much attention. However, the impact of reactive oxygen species, and the enzymes that control their production, on neutrophil recruitment and function is not well understood. Using congenic mice with varying levels of extracellular superoxide dismutase (ecSOD) activity, we have recently shown that the presence of ecSOD decreases clearance of L. monocytogenes while increasing the recruitment of neutrophils that are not protective in the liver. The data presented here show that ecSOD activity does not lead to a cell-intrinsic increase in neutrophil-homing potential or a decrease in protection against L. monocytogenes. Instead, ecSOD activity enhances the production of neutrophil-attracting factors and protects hyaluronic acid (HA) from damage. Furthermore, neutrophils from the livers of ecSOD-expressing mice have decreased intracellular and surface-bound myeloperoxidase, are less capable of killing phagocytosed L. monocytogenes, and have decreased oxidative burst. Collectively, our data reveal that ecSOD activity modulates neutrophil recruitment and function in a cell-extrinsic fashion, highlighting the importance of the enzyme in protecting tissues from oxidative damage. Listeria monocytogenes is a Gram-positive bacterium that can be found in the soil, fruits, vegetables, meats, and dairy products. Ingestion of L. monocytogenes-contaminated foods can cause spontaneous abortions in pregnant women, as well as septicemia, meningitis, and gastroenteritis, primarily in immunocompromised individuals (1). Surprisingly, clinical listeriosis results in an ϳ25% mortality rate despite the use of antibiotics (1), which makes understanding the immune response against the pathogen important. Furthermore, L. monocytogenes is a widely used model pathogen to study and understand host-pathogen interactions due to its ease of use and manipulation.Neutrophils are short-lived immune cells that differentiate in the bone marrow from the common myeloid progenitor (2). Under normal homeostatic conditions, most neutrophils are retained in the bone marrow until inflammation leads to signaling for their egress. One of the mechanisms by which neutrophils are recruited out of the bone marrow and into tissues is through the increased production of CXCL1 and CXCL2 (3, 4), which are both induced by the interleukin 23 (IL-23)/IL-17 pathway (5, 6). During lipopolysaccharide (LPS)-induced hepatic injury, hyaluronic acid (HA)-CD44 interactions faci...

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Extracellular Superoxide Dismutase Inhibits Innate Immune Responses and Clearance of an Intracellular Bacterial Infection

Cited by 46 publications

References 46 publications

Antioxidant Defenses of Francisella tularensis Modulate Macrophage Function and Production of Proinflammatory Cytokines

Antioxidant Defenses of Francisella tularensis Modulate Macrophage Function and Production of Proinflammatory Cytokines

Pyruvate-Dependent Changes in Neutrophil Amino- and Alpha-Keto Acid Profiles or Immunity: Which Mechanisms Are Involved?

Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver

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