A Critical Role for C5L2 in the Pathogenesis of Experimental Allergic Asthma

Zhang, Xun; Schmudde, Inken; Laumonnier, Yves; Pandey, Manoj Kumar; Clark, Jennifer; König, Peter; Gerard, Norma P.; Gérard, Craig; Wills‐Karp, Marsha; Köhl, Jörg

doi:10.4049/jimmunol.1000892

Cited by 85 publications

(94 citation statements)

References 54 publications

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“…1 In addition to C5aR, C5a can also interact with a second receptor, C5L2, which controls the development of Th1 and Th17 cells in experimental allergic asthma at the DC/T cell interface and promotes Th2 immune responses independent of pulmonary DCs. 36 This effect may become dominant in vivo in the absence of C5aR. Finally, C5aR signaling in BMDCs may inappropriately reflect C5aR-mediated regulation of the distinct pulmonary DC subsets in vivo.…”

Section: Discussionmentioning

confidence: 99%

C5a receptor signalling in dendritic cells controls the development of maladaptive Th2 and Th17 immunity in experimental allergic asthma

et al. 2013

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Section: Discussionmentioning

confidence: 99%

C5a receptor signalling in dendritic cells controls the development of maladaptive Th2 and Th17 immunity in experimental allergic asthma

et al. 2013

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“…OVA-sensitized C5L2-deficient mice exhibit reduced AHR, inflammatory cell infiltration, and airway inflammation (Chen et al, 2007). Similarly, HDM-sensitized C5L2-deficient mice show significantly attenuated AHR and airway inflammation that is associated with decreased mucus production, Th2 cytokine production, and serum IgE levels (Zhang et al, 2010), confirming the pro-inflammatory role of C5L2 in the development of asthma. The available data further indicates that C5L2 also has a regulatory impact on mDCs.…”

Section: Allergic Inflammation: Allergic Asthmamentioning

confidence: 68%

“…Taken together this suggests that C5a/C5aR complex controls IL-17A by limiting IL-23 production (Lajoie et al, 2010). As described above, Th17 development in experimental asthma is not only regulated by C5aR but by C5L2 as well (Zhang et al 2010). In addition to its impact on Th17 cells, C5a may also regulate the development of T regs (Palomares et al, 2010).…”

Section: Allergic Inflammation: Allergic Asthmamentioning

confidence: 69%

“…Moreover, HDM stimulation of C5L2-deficient mDCs results in production of the Th17-promoting cytokine IL-23. Collectively, this suggests a complex role of C5L2 in asthma; controlling the development of Th1 and Th17 cells in response to allergen challenge as well as driving the Th2 immune response (Zhang et al, 2010). Th17 are IL-17A-producing subset of CD4 + T cells which have received much interest recently in allergy research.…”

Section: Allergic Inflammation: Allergic Asthmamentioning

confidence: 99%

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Complement Receptors in Inflammation

Pundir¹,

Kulka²

2012

Inflammation, Chronic Diseases and Cancer - Cell and Molecular Biology, Immunology and Clinical Bases

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“…Owing in part to the previously enigmatic functions of C5aR2, and a predominant focus on C5aR1, the potential for C5aR2 to be targeted therapeutically remains largely unexplored. To date, animal knockout studies have demonstrated an effect of C5aR2 modulation in spinal injury, allergic asthma, and sepsis (Biggins et al 2017;Rittirsch et al 2008;Zhang et al 2010;Li et al 2013). …”

Section: Targeting Of C5ar2mentioning

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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A Critical Role for C5L2 in the Pathogenesis of Experimental Allergic Asthma

Abstract: Material Supplementary 2.DC1http://www.jimmunol.org/content/suppl/2010/10/25/jimmunol.100089References

Cited by 85 publications

References 54 publications

C5a receptor signalling in dendritic cells controls the development of maladaptive Th2 and Th17 immunity in experimental allergic asthma

C5a receptor signalling in dendritic cells controls the development of maladaptive Th2 and Th17 immunity in experimental allergic asthma

Complement Receptors in Inflammation

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

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