Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases—C3 or C5 emerge together with CD14 as promising targets

Barratt‐Due, Andreas; Pischke, Søren Erik; Nilsson, Per H.; Espevik, Terje; Mollnes, Tom Eirik

doi:10.1189/jlb.3vmr0316-132r

Cited by 50 publications

(67 citation statements)

References 100 publications

(91 reference statements)

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“…Previous reports of bacteria- and meconium-induced inflammation clearly demonstrate that IL-6 is highly CD14-dependent whereas IL-1β has been shown to be both CD14- and complement-dependent [10, 23]. Although these immune pathways act partly independent, they are mutually connected by considerable cross-talk, implying that a combined inhibition of the pathways inherit a pronounced anti-inflammatory potential for exogenously as well as endogenously induced inflammation [11]. The complement inhibitor used in this study, SOBI002, efficiently and completely prevented systemic sC5b-9 formation, and thus also the formation of the potent anaphylatoxin C5a.…”

Section: Discussionmentioning

confidence: 99%

“…In whole blood, meconium-induced inflammation is differentially attenuated by inhibition of either the complement or the accessory TLR molecule, CD14, but is abolished by their combined inhibition [9, 10]. Although complement and TLRs act independently, they are connected through mutual interaction and extensive cross-talk, so a combined blockage of these branches represents a potential pronounced anti-inflammatory action on downstream inflammatory responses [9, 11]. …”

Section: Introductionmentioning

confidence: 99%

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Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome

et al. 2018

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Background: Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors. Objectives: To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model. Methods: Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA. Results: SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1β and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14. Conclusion: Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome

et al. 2018

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“…We found that the TLR-4 inhibitor eritoran completely inhibited LPS-induced, but did not significantly reduce the E. coli-induced, TF surface expression. CD14 blockade has a broader effect on several TLRs than inhibition of TLR-4 by eritoran as CD14 is a co-receptor of several TLRs, including TLR-2 and -4 [39]. E. coli bacteria also activates TLR-2 [38].…”

Section: Discussionmentioning

confidence: 99%

Complement component 5 does not interfere with physiological hemostasis but is essential forEscherichia coli-induced coagulation accompanied by Toll-like receptor 4

Landsem

Fure

Ludviksen

et al. 2018

Clinical and Experimental Immunology

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Summary There is a close cross‐talk between complement, Toll‐like receptors (TLRs) and coagulation. The role of the central complement component 5 (C5) in physiological and pathophysiological hemostasis has not, however, been fully elucidated. This study examined the effects of C5 in normal hemostasis and in Escherichia coli‐induced coagulation and tissue factor (TF) up‐regulation. Fresh whole blood obtained from six healthy donors and one C5‐deficient individual (C5D) was anti‐coagulated with the thrombin inhibitor lepirudin. Blood was incubated with or without E. coli in the presence of the C5 inhibitor eculizumab, a blocking anti‐CD14 monoclonal antibody (anti‐CD14) or the TLR‐4 inhibitor eritoran. C5D blood was reconstituted with purified human C5. TF mRNA was measured by quantitative polymerase chain reaction (qPCR) and monocyte TF and CD11b surface expression by flow cytometry. Prothrombin fragment 1+2 (PTF1·2) in plasma and microparticles exposing TF (TF‐MP) was measured by enzyme‐linked immunosorbent assay (ELISA). Coagulation kinetics were analyzed by rotational thromboelastometry and platelet function by PFA‐200. Normal blood with eculizumab as well as C5D blood with or without reconstitution with C5 displayed completely normal biochemical hemostatic patterns. In contrast, E. coli‐induced TF mRNA and TF‐MP were significantly reduced by C5 inhibition. C5 inhibition combined with anti‐CD14 or eritoran completely inhibited the E. coli‐induced monocyte TF, TF‐MP and plasma PTF1·2. Addition of C5a alone did not induce TF expression on monocytes. In conclusion, C5 showed no impact on physiological hemostasis, but substantially contributed to E. coli‐induced procoagulant events, which were abolished by the combined inhibition of C5 and CD14 or TLR‐4.

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“…However, while blocking CD14 has been shown to reduce the production of proinflammatory cytokines [20, 21] and to have promising clinical effects [22-24], inflammation still persists. It has recently been suggested that the combined inhibition of CD14 and complement may be more effective in this respect [25, 26]. …”

Section: Introductionmentioning

confidence: 99%

CD14 Counterregulates Lipopolysacharide-Induced Tumor Necrosis Factor-α Production in a Macrophage Subset

et al. 2019

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In response to GM-CSF or M-CSF, macrophages (MΦ) can acquire pro- or anti-inflammatory properties, respectively. Given the importance of CD14 and Toll-like receptor (TLR) 4 in lipopolysaccharide (LPS)-induced signaling, we studied the effect of anti-CD14 antibody mediated CD14 blockade on LPS-induced cytokine production, signal transduction and on the expression levels of CD14 and TLR4 in GM-MΦ and M-MΦ. We found M-MΦ to express higher levels of both surface antigens and to produce more interferon (IFN)-β and interleukin-10, but less tumor necrosis factor (TNF)-α than GM-MΦ. Blockage of CD14 at high LPS concentrations increased the production of proinflammatory cytokines and decreased that of IFN-β in M-MΦ but not in GM-MΦ. We show that phosphorylation states of signaling molecules of the MyD88 (myeloid differentiation primary response 88), TRIF (TIR-domain-containing adapter-inducing IFN-β) and MAPK (mitogen-activated protein kinase) pathways are not altered in any way that would account for the cytokine overshoot reaction. However, CD14 blockage in M-MΦ decreased TLR4 and CD14 expression levels, regardless of the presence of LPS, indicating that the loss of the surface molecules prevented LPS from initiating TRIF signaling. As TNF-α synthesis was even upregulated under these experimental conditions, we suggest that TRIF is normally involved in restricting LPS-induced TNF-α overproduction. Thus, surface CD14 plays a decisive role in the biological response by determining LPS-induced signaling.

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Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases—C3 or C5 emerge together with CD14 as promising targets

Abstract: Review of how targeting key upstream molecules at the recognition phase of innate immunity exert anti-inflammatory effects; a potential therapeutic regimen for inflammatory diseases.

Cited by 50 publications

References 100 publications

Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome

Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome

Complement component 5 does not interfere with physiological hemostasis but is essential forEscherichia coli-induced coagulation accompanied by Toll-like receptor 4

CD14 Counterregulates Lipopolysacharide-Induced Tumor Necrosis Factor-α Production in a Macrophage Subset

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