Macrophage-intrinsic regulators of tissue type 2 in ammation
Julia Esser-von Bieren, Center of Allergy and Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Center Munich
Caspar Ohnmacht, Center of Allergy and Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Center Munich
Expression of transglutaminase 2 (brown staining) in airway tissue of house dust mite allergic patients and potential crosstalk between macrophage-intrinsic TG2 and AhR in type 2 inflammation: Whilst allergens or endogenous tissue factors (e.g. IL-4, retinoic acid) trigger TG2 expression, thus contributing to the initiation of type 2 inflammation, other factors (e.g. tryptophan metabolites) may activate the AhR system to counter-regulate type 2 inflammation. Both TG2 and the AhR system may regulate type 2 immune responses via modulating the lipid mediator metabolism in macrophages. A potential crosstalk between the AhR and TG2 has been reported for other disease settings, but has not been investigated in type 2 immune responses. Pathways or mediators with predominantly anti-inflammatory roles in airway allergy are shown in green, whilst red indicates pro-inflammatory roles.
Subproject 7 aims to define how (macrophage-intrinsic) Transglutaminase-2 and the aryl hydrocarbon receptor (AhR) regulate type-2 immune responses.
In particular, we aim to investigate the role of TG2 as an epigenetic regulator of macrophage activation and function. Thus, we are studying how myeloid and hematopoietic TG2 may contribute to central trained immunity, inflammation and host defense in allergic asthma and helminth infection. Using pharmacological inhibitors, siRNA-mediated knock-down and CRISPR-driven genetic ablation of TG2 in human cells, we further aim to translate mechanistic insights form murine models of type-2 immunity to human disease such as allergic asthma.
So far, we found that the AhR regulates lipid mediator pathways in macrophages that are important for type-2 immunity, prompting us to determine the mechanisms underlying this regulation as well as to identify the consequences for type-2 immune responses. Using different approaches including pharmacological inhibitors and conditional knockout animals we aim to investigate whether the AhR is a direct regulator of genes relevant for lipid mediator synthesis or whether a different genetic program during macrophage differentiation in the absence of AhR signaling is responsible for such effects. We also aim to identify co-factors that contribute to the AhR-mediated regulation of lipid mediator production in macrophages. Finally, we aim to validate these findings during in vivo settings of type-2 inflammation.
Both parts will be done in close collaboration with the groups of Peter Murray, David Voehringer and Michael Sieweke.
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