Past, Present, and Future of Augmentation of Monocyte Function in the Surgical Patient

Galbraith, Norman; Carter, Jane; Polk, Hiram C.

doi:10.1089/sur.2016.014

Cited by 20 publications

(17 citation statements)

References 35 publications

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“…Neutrophil dysfunction and direct neutrophil-mediated organ injury have been proposed to contribute to septic inflammatory organ injury (13). However, impaired cell-autonomous monocyte/macrophage function appears to be primarily responsible for the insufficient antibacterial defenses in the septic host (14)(15)(16). In addition, septic monocytes and macrophages are decreased in their ability to respond ex vivo to LPS or other stimuli by producing antibacterial cytokines, such as IL-6 and IL-12 (17,18).…”

Section: Introductionmentioning

confidence: 99%

Macrophage P2X4 receptors augment bacterial killing and protect against sepsis

et al. 2018

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The macrophage is a major phagocytic cell type, and its impaired function is a primary cause of immune paralysis, organ injury, and death in sepsis. An incomplete understanding of the endogenous molecules that regulate macrophage bactericidal activity is a major barrier for developing effective therapies for sepsis. Using an in vitro killing assay, we report here that the endogenous purine ATP augments the killing of sepsis-causing bacteria by macrophages through P2X4 receptors (P2X4Rs). Using newly developed transgenic mice expressing a bioluminescent ATP probe on the cell surface, we found that extracellular ATP levels increase during sepsis, indicating that ATP may contribute to bacterial killing in vivo. Studies with P2X4R-deficient mice subjected to sepsis confirm the role of extracellular ATP acting on P2X4Rs in killing bacteria and protecting against organ injury and death. Results with adoptive transfer of macrophages, myeloid-specific P2X4R-deficient mice, and P2rx4 tdTomato reporter mice indicate that macrophages are essential for the antibacterial, antiinflammatory, and organ protective effects of P2X4Rs in sepsis. Pharmacological targeting of P2X4Rs with the allosteric activator ivermectin protects against bacterial dissemination and mortality in sepsis. We propose that P2X4Rs represent a promising target for drug development to control bacterial growth in sepsis and other infections.

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Section: Introductionmentioning

confidence: 99%

Macrophage P2X4 receptors augment bacterial killing and protect against sepsis

et al. 2018

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“…Impaired monocyte function is one facet of immune dysregulation that continues to be recognized as a central tenant of trauma- or sepsis-related immunosuppression [ 5 , 6 ]. However, efforts to pharmacologically modulate this response have failed to consistently improve mortality and have, therefore, not secured a place in the armory of the compleat surgeon [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

IκK-16 decreases miRNA-155 expression and attenuates the human monocyte inflammatory response

et al. 2017

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Excessive inflammatory responses in the surgical patient may result in cellular hypo-responsiveness, which is associated with an increased risk of secondary infection and death. microRNAs (miRNAs), such as miR-155, are powerful regulators of inflammatory signalling pathways including nuclear factor κB (NFκB). Our objective was to determine the effect of IκK-16, a selective blocker of inhibitor of kappa-B kinase (IκK), on miRNA expression and the monocyte inflammatory response. In a model of endotoxin tolerance using primary human monocytes, impaired monocytes had decreased p65 expression with suppressed TNF-α and IL-10 production (P < 0.05). miR-155 and miR-138 levels were significantly upregulated at 17 h in the impaired monocyte (P < 0.05). Notably, IκK-16 decreased miR-155 expression with a corresponding dose-dependent decrease in TNF-α and IL-10 production (P < 0.05), and impaired monocyte function was associated with increased miR-155 and miR-138 expression. In the context of IκK-16 inhibition, miR-155 mimics increased TNF-α production, while miR-155 antagomirs decreased both TNF-α and IL-10 production. These data demonstrate that IκK-16 treatment attenuates the monocyte inflammatory response, which may occur through a miR-155-mediated mechanism, and that IκK-16 is a promising approach to limit the magnitude of an excessive innate inflammatory response to LPS.

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“…With improvements to patient care, sepsis has transitioned from a hyper-inflammatory disorder to an immunosuppressive disorder, with almost 70% of deaths occurring after the initial inflammatory phase due to the subsequent impaired immunity that make patients more vulnerable to infection recurrence or nosocomial infections (21). Current treatment strategies for sepsis are now not only aimed at treating the initial systemic infection but also at preventing cellular apoptosis and boosting host immunity (22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Development of Systemic Immune Dysregulation in a Rat Trauma Model with Biomaterial-Associated Infection

Vantucci

Ahn

Schenker

et al. 2020

Preprint

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Orthopedic biomaterial-associated infections remain a large clinical challenge, particularly with open fractures and segmental bone loss. Invasion and colonization of bacteria within immuneprivileged canalicular networks of the bone can lead to local, indolent infections that can persist for years without symptoms before eventual catastrophic hardware failure. Host immunity is essential for bacterial clearance and an appropriate healing response, and recent evidence has suggested an association between orthopedic trauma and systemic immune dysregulation and immunosuppression. However, the impact of a local infection on this systemic immune response and subsequent effects on the local response is poorly understood and has not been a major focus for addressing orthopedic injuries and infections. Therefore, this study utilized a model of orthopedic biomaterial-associated infection to investigate the effects of infection on the longterm immune response. Here, despite persistence of a local, indolent infection lacking outward symptoms, there was still evidence of long-term immune dysregulation with systemic increases in MDSCs and decreases in T cells compared to non-infected trauma. Further, the trauma only group exhibited a regulated and coordinated systemic cytokine response, which was not present in the infected trauma group. Locally, the infection group had attenuated macrophage infiltration in the local soft tissue compared to the non-infected group. Our results demonstrate widespread impacts of a localized orthopedic infection on the systemic and local immune responses.Characterization of the immune response to orthopedic biomaterial-associated infection may identify key targets for immunotherapies that could optimize both regenerative and antibiotic interventions, ultimately improving outcomes for these patients.

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Past, Present, and Future of Augmentation of Monocyte Function in the Surgical Patient

Cited by 20 publications

References 35 publications

Macrophage P2X4 receptors augment bacterial killing and protect against sepsis

Macrophage P2X4 receptors augment bacterial killing and protect against sepsis

IκK-16 decreases miRNA-155 expression and attenuates the human monocyte inflammatory response

Development of Systemic Immune Dysregulation in a Rat Trauma Model with Biomaterial-Associated Infection

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