Complement Inhibition Promotes Endogenous Neurogenesis and Sustained Anti-Inflammatory Neuroprotection following Reperfused Stroke

Ducruet, Andrew F.; Zacharia, Brad E.; Sosunov, Sergey A.; Gigante, Paul R.; Yeh, Mason L.; Górski, J; Otten, Marc L.; Hwang, Richard Y.; DeRosa, Peter; Hickman, Zachary L.; Sergot, Paulina; Connolly, E. Sander

doi:10.1371/journal.pone.0038664

Cited by 70 publications

(63 citation statements)

References 35 publications

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“…Based on the effects of a low-dose C3aR antagonist treatment, Connely and co-workers concluded that C3aR inhibition attenuates brain injury after cerebral hemorrhage and ischemia/ reperfusion via reducing granulocyte infiltration [49,50], as well as suppression of T-lymphocyte infiltration and stimulation of neuroblast proliferation [51]. Given the fact that SB 290157, the C3aR antagonist used in these studies, has a full agonist activity on C3aR in a variety of cell systems, in particular in cells with high receptor density [52], interpretation of results obtained with SB 290157 should be done with caution.…”

Section: Discussionmentioning

confidence: 99%

Complement Peptide C3a Promotes Astrocyte Survival in Response to Ischemic Stress

et al. 2015

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Astrocytes are the most numerous cells in the central nervous system with a range of homeostatic and regulatory functions. Under normal conditions as well as after ischemia, astrocytes promote neuronal survival. We have previously reported that the complement-derived peptide C3a stimulates neuronal differentiation of neural progenitor cells and protects the immature brain tissue against hypoxic-ischemic injury. Here, we studied the effects of C3a on the response of mouse cortical astrocytes to ischemia. We have found that chemical ischemia, induced by combined inhibition of oxidative phosphorylation and glycolysis, upregulates the expression of C3a receptor in cultured primary astrocytes. C3a treatment protected wild-type but not C3a receptor-deficient astrocytes from cell death induced by chemical ischemia or oxygen-glucose deprivation by reducing ERK signaling and caspase-3 activation. C3a attenuated ischemia-induced upregulation of glial fibrillary acidic protein; however, the protective effects of C3a were not dependent on the presence of the astrocyte intermediate filament system. Pre-treatment of astrocytes with C3a during recovery abrogated the ischemia-induced neuroprotective phenotype of astrocytes. Jointly, these results provide the first evidence that the complement peptide C3a modulates the response of astrocytes to ischemia and increases their ability to cope with ischemic stress.

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Section: Discussionmentioning

confidence: 99%

Complement Peptide C3a Promotes Astrocyte Survival in Response to Ischemic Stress

et al. 2015

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“…A number of animal and human studies [29][30][31][32][33][34][35][36][37][38][39] , including our own [40][41][42] , demonstrated that activation of the complement system play a decisive role in the pathophysiology of IS. No study has reported data on functional state of FH and FL in this disorder.…”

Section: Discussionmentioning

confidence: 99%

Collectins, C3 complement protein, annexin V and C-reactive protein in acute ischemic stroke: interrelation and implication to upregulated apoptosis and inflammation

Boyajyan

Tsakanova

Sim

2014

Inflamm Cell Signal

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Upregulated inflammatory response and apoptosis, both triggered by ischemia, are the most destructive pathologic processes developed after acute ischemic stroke (IS) at both central and peripheral levels. Identification of molecular mediators of these processes and understanding of their pathomechanisms will support the development of therapies, which can significantly improve outcomes of IS-affected subjects.Mannan-binding lectin (MBL), ficolin L (FL), ficolin H (FH) and C3 complement proteins participate in apoptotic cells recognition and clearance through various mechanisms. In the present study we performed comparative determination of the blood levels of MBL, FL and FH, and hemolytic activity of C3 protein (C3H50) as well as apoptosis marker protein, circulating annexin V (cANXV), and inflammatory marker C-reactive protein (CRP) in 99 patients with acute IS on the first day of stroke onset and 110 healthy subjects. Potential correlation between all measured parameters was analyzed. Methods included enzyme-linked immunosorbent, hemolytic, and immunonephelometric assays; statistics were performed by Student's t-test and Pearson's correlation analysis. The obtained data demonstrated significantly increased and correlated with each other blood levels of MBL and C3H50, cANXV and CRP in patients compared to controls. Slight, while significant, changes in the blood levels of FL and FH were also observed. We concluded that post-ischemic response at the first day of IS onset is characterized by sufficiently elevated and positively correlated with each other blood levels of MBL, C3H50, cANXV and CRP as well as by slightly increased blood levels of FH and FL. The obtained results suggest that MBL and C3 protein are implicated in upregulated inflammatory response and apoptosis developed after IS onset at a peripheral level, and that these pathological processes are interrelated and interdependent.

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“…For example, both C5aR1 and C3aR signalling have been shown to play unique roles in the control of a number of non-immune stem cell populations, including prenatal, adult, and cancer cells . In regulation of these cell populations, in vivo animal studies have shown benefit of C3aR modulation in the treatment brain injury (Järlestedt et al 2013;Ducruet et al 2012), and of both C3aR and C5aR1 modulation in the control of tumour growth Corrales et al 2012;Sayegh, Bloch, and Parsa 2014). …”

Section: The Future Of Anaphylatoxin Targeted Therapeuticsmentioning

confidence: 99%

Exploring the role of C5a-C5aR1 signalling in development through pluripotent stem cell modelling

Hawksworth¹

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The complement system has been traditionally described as a powerful controller of innate immunity.With activation through the recognition of pathogenic surfaces, spontaneous hydrolysis, or extrinsic cleavage, a cleavage cascade is initiated culminating in the formation of the active complement fragments C3a, C3b, C5a, and C5b. These fragments direct immune cells to sites of inflammation, as well as tagging pathogens for destruction and directly lysing foreign cells. It is now clear however, that this complex family of proteins possesses a wide range of functions outside of immune regulation. From fertilisation and morphogenesis, to the control of foetal and adult stem cell populations, studies have described novel actions of complement factors. This thesis is focussed on the central complement receptor, C5aR1. Traditionally described as a potent activating and chemotactic receptor for immune cells, C5aR1 has been shown to function in a number of nonimmune cell populations. Of note, our laboratory has previously described a role for C5aR1 in neural tube closure, with loss of C5aR1 signalling associated with increased neural tube defects under folate deficient conditions. However, a mechanistic role of C5aR1 at this stage of development was not described.In this thesis, pluripotent stem cells were utilised as an in vitro model of human development to interrogate the expression and function of C5aR1 at a number of developmental stages. Specifically, in pluripotent stem cells representative of the blastocyst inner cell mass, in neural rosettes representative of the developing ventricular zone, and in matured post-mitotic cortical neurons. This builds on previous work by our laboratory, which had identified C5aR1 actions in the mouse ventricular zone, analogous to late neural rosette cultures, and had shown a neurotoxic effect of C5aR1 in post-mitotic mouse neurons.C5aR1 was found to be expressed in pluripotent stem cells, with a role in promoting maintenance of pluripotency in the absence of FGF2 signalling. Additionally, C5aR1 was found to be apically expressed in human neural rosettes, with signalling promoting proliferation and maintenance of cell polarity. This work correlated well with mouse studies performed outside of this thesis, to show that in vivo, loss of C5aR1 in this neural progenitor population resulted in behavioural deficits and microstructural brain changes. Lastly, we determined the mRNA expression of C5aR1 in human postmitotic cortical neurons. However, in contrast to previous mouse studies, exogenous C5a, alone or in the presence of secondary stressors, had little effect on the survival of these cells.Overall, the results presented in this thesis have further expanded our knowledge of C5a-C5aR1 signalling in development, describing novel roles for this signalling pathway. The use of pluripotent stem cells allowed for the exploration of C5aR1 actions in human development that would otherwise be limited to animal models. Additionally, it allowed for the correlation of previous animal resu...

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Complement Inhibition Promotes Endogenous Neurogenesis and Sustained Anti-Inflammatory Neuroprotection following Reperfused Stroke

Cited by 70 publications

References 35 publications

Complement Peptide C3a Promotes Astrocyte Survival in Response to Ischemic Stress

Complement Peptide C3a Promotes Astrocyte Survival in Response to Ischemic Stress

Collectins, C3 complement protein, annexin V and C-reactive protein in acute ischemic stroke: interrelation and implication to upregulated apoptosis and inflammation

Exploring the role of C5a-C5aR1 signalling in development through pluripotent stem cell modelling

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