Macrophage-Produced IL-12p70 Mediates Hemorrhage-Induced Damage in a Complement-Dependent Manner

Hylton, Diana J.; Hoffman, Sara M.; Rooijen, Nico van; Tomlinson, Stephen; Fleming, Sherry D.

doi:10.1097/shk.0b013e3181ed8ec9

Cited by 9 publications

(17 citation statements)

References 34 publications

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“…1). Similar to previous studies (8), wild type mice sustained significant intestinal damage at 2h post-hemorrhage (HEM). In contrast, Tlr2 -/- mice received significantly less damage than wild type mice when subjected to hemorrhage.…”

Section: Resultssupporting

confidence: 85%

“…Previous studies indicated that blood loss due to hemorrhage can induce intestinal damage and inflammation (8). To determine if TLR2 is required for this tissue damage, we removed 30% of the calculated blood volume from wild type (C57Bl/6) and Tlr2 -/- mice and analyzed intestinal villus injury at 2h post-hemorrhage.…”

Section: Resultsmentioning

confidence: 99%

“…The inflammatory infiltrate is critical to hemorrhage induced tissue damage in multiple organs (6, 8, 10-12). Multiple aspects of the inflammatory response have been implicated in the tissue damage from neutrophils to toll-like receptors (TLRs) to complement activation.…”

Section: Introductionmentioning

confidence: 99%

“…The neutrophilic infiltrate of the liver and lung produces an oxidative burst that is critical to the innate immune system's response to pathogen associated molecular patterns (PAMPs). Hemorrhage induces multiple pro-inflammatory cytokines, including TNFα, IL-6 and IL-12 in a TLR-dependent manner (8, 13). Multiple TLRs are up-regulated in response to hemorrhage (11-14) and TLR4 and TLR9 appear to have unique roles in hemorrhage (10, 12, 13, 15, 16).…”

Section: Introductionmentioning

confidence: 99%

“…For example, in rat models, complement C3 depletion prevents clinical signs of hemorrhagic shock and complement activation is critical for tissue damage to occur as a result of hemorrhage (22). Importantly, complement inhibitors including C1 inhibitor (9), C5a receptor antagonist, (21), soluble complement receptor 1 (CR1) (23) and complement receptor 2-factor H (CR2-factor H) (8) attenuate hemorrhage-induced intestinal damage in wild type animals. Recent studies demonstrated that during hemorrhage complement induces IL-12p70 production and TLR2 is required for the complement mediated intestinal damage in response to ischemia/reperfusion injury.…”

Section: Introductionmentioning

confidence: 99%

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TLR2 Regulates Complement-Mediated Inflammation Induced by Blood Loss During Hemorrhage

Goering

Pope

Fleming

2016

Shock

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Hemorrhagic shock resulting from blood loss directs the majority of the blood to the vital organs, dramatically reducing blood flow to the intestines and resulting in damage and inflammation. The excessive intestinal inflammatory response includes pro-inflammatory cytokines and complement activation, although the mechanism is not clear. Toll-like receptors play a vital role in the innate immune response and toll-like receptor 2 (TLR2) is required for intestinal ischemia/reperfusion-induced injury. We hypothesized that TLR2 plays an integral role in the intestinal inflammatory response after hemorrhage and subjected C57Bl/6 wild type and Tlr2-/- mice to atraumatic loss of ∼30% total blood volume. Two hours after blood removal, the intestinal injury and inflammation were assessed. We demonstrate that compared to wild type control mice, Tlr2-/- mice sustain less intestinal damage and inflammation. Importantly, TLR2 regulated eicosanoid and complement activation andIL-12 and TNFα secretions, indicating interactions between TLR2 and complement in response to significant blood loss.

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Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

TLR2 Regulates Complement-Mediated Inflammation Induced by Blood Loss During Hemorrhage

Goering

Pope

Fleming

2016

Shock

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CR2-Mediated Targeting of Complement Inhibitors: Bench-to-Bedside Using a Novel Strategy for Site-Specific Complement Modulation

Holers

Rohrer

Tomlinson

2012

Complement Therapeutics

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Recent approval of the first human complement pathway-directed therapeutics, along with high-profile genetic association studies, has catalyzed renewed biopharmaceutical interest in developing drugs that modulate the complement system. Substantial challenges remain, however, that must be overcome before widespread application of complement inhibitors in inflammatory and autoimmune diseases becomes possible. Among these challenges are the following: (1) defining the complement pathways and effector mechanisms that cause tissue injury in humans and determining whether the relative importance of each varies by disease, (2) blocking or modulating, using traditional small molecule or biologic approaches, the function of complement proteins whose circulating levels are very high and whose turnover rates are relatively rapid, especially in the setting of acute and chronic autoimmune diseases, and (3) avoiding infectious complications or impairment of other important physiological functions of complement when using systemically active complement-blocking agents. This chapter will review data that address these challenges to therapeutic development, with a focus on the development of a novel strategy of blocking specific complement pathways by targeting inhibitors using a recombinant portion of the human complement receptor type 2 (CR2/CD21) which specifically targets to sites of local complement C3 activation where C3 fragments are covalently fixed. Recently, the first of these CR2-targeted proteins has entered human phase I studies in the human disease paroxysmal nocturnal hemoglobinuria. The results of murine translational studies using CR2-targeted inhibitors strongly suggest that a guiding principle going forward in complement therapeutic development may well be to focus on developing strategies to modulate the pathway as precisely as possible by physically localizing therapeutic inhibitory effects.

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Tissue-targeted complement therapeutics

Tomlinson

Thurman

2018

Molecular Immunology

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Complement activation contributes to the pathogenesis of numerous inflammatory and autoimmune diseases. Therapeutic complement inhibitors have proven effective in several of these diseases and have now entered clinical use. Complement activation has multiple different biologic effects, however, and the currently available drugs can have undesirable side-effects, such as an increased risk of infection. Several different complement inhibitors have been developed that bind to target molecules, thereby concentrating the drug at a specific anatomic site. This approach appears to be both more effective than untargeted drugs and to have fewer side effects. In this article we review different targeting strategies that have been developed and the evidence supporting the use and benefits of targeted drugs.

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Macrophage-Produced IL-12p70 Mediates Hemorrhage-Induced Damage in a Complement-Dependent Manner

Cited by 9 publications

References 34 publications

TLR2 Regulates Complement-Mediated Inflammation Induced by Blood Loss During Hemorrhage

TLR2 Regulates Complement-Mediated Inflammation Induced by Blood Loss During Hemorrhage

CR2-Mediated Targeting of Complement Inhibitors: Bench-to-Bedside Using a Novel Strategy for Site-Specific Complement Modulation

Tissue-targeted complement therapeutics

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