FOR2599Project 7

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

human lung section stained for DAPI (blue), CC10 (green) and the AhR large gene CYP1B1 (red)

Lung tissue of a helminth infected mouse

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.

Summary

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.

Selected Publications

de Los Reyes Jiménez M, Lechner A, Alessandrini F, Bohnacker S, Schindela S, Trompette A, Haimerl P, Thomas D, Henkel F, Mourão A, Geerlof A, da Costa CP, Chaker AM, Brüne B, Nüsing R, Jakobsson PJ, Nockher WA, Feige MJ, Haslbeck M, Ohnmacht C, Marsland BJ, Voehringer D, Harris NL, Schmidt-Weber CB, Esser-von Bieren J. (2020) An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products, Science Translational Medicine, 12(540)

Haimerl P, Bernhard U, Schindela S, Henkel FDR, Lechner A, Zissler UM, Pastor X, Thomas D, Cécil A, Ge Y, Haid M, Prehn C, Tokarz J, Heinig M, Adamski J, Schmidt-Weber CB, Chaker AM, Esser-von Bieren J (2020). Inflammatory macrophage memory in NSAID-exacerbated respiratory disease, J Allergy Clin Immunol (6) S0091-6749(20)30803-4

Coakley G, Volpe B, Bouchery T, Shah K, Butler A, Geldhof P, Hatherill M, Horsnell WGC, Esser-von Bieren J, Harris NL. (2020), Immune serum-activated human macrophages coordinate with eosinophils to immobilize Ascaris suum larvae, Parasite Immunol.; (7) 42(7):e12728.

Henkel FDR, Friedl A, Haid M, Thomas D, Bouchery T, Haimerl P, de Los Reyes Jiménez M, Alessandrini F, Schmidt-Weber CB, Harris NL, Adamski J, Esser-von Bieren J (2019) House dust mite drives pro-inflammatory eicosanoid reprogramming and macrophage effector functions. Allergy, 74(6):1090-1101.

Andreas N, Potthast M, Geiselhöringer AL, Garg G, de Jong R, Riewaldt J, Russkamp D, Riemann M, Girard JP, Blank S, Kretschmer K, Schmidt-Weber C, Korn T, Weih F, Ohnmacht C. (2019) RelB Deficiency in Dendritic Cells Protects from Autoimmune Inflammation Due to Spontaneous Accumulation of Tissue T Regulatory Cells, J Immunol 15;203(10):2602-2613.

Dietz K, de los Reyes Jiménez M, Gollwitzer ES, Chaker A, Zissler UM, Rådmark OP, Baarsma HA, Königshoff M, Schmidt-Weber CB, Marsland BJ, Esser-von Bieren J, Age dictates a steroid resistant cascade of Wnt5a, transglutaminase-2 and leukotrienes in inflamed airways, J Allergy Clin Immunol 2017.139(4):1343-1354.e6.

Esser-von Bieren, J., B. Volpe, D.B. Sutherland, J. Burgi, J.S. Verbeek, B.J. Marsland, J.F. Urban, Jr., and N.L. Harris, Immune antibodies and helminth products drive CXCR2-dependent macrophage-myofibroblast crosstalk to promote intestinal repair. PLoS Pathog 2015. 11(3): p. e1004778.

Esser J, Gehrmann U, D'Alexandri FL, Hidalgo-Estévez AM, Wheelock CE, Scheynius A, Gabrielsson S, Rådmark O. Exosomes from human macrophages and dendritic cells contain enzymes for leukotriene biosynthesis and promote granulocyte migration. J Allergy Clin Immunol 2010. 126(5):1032-40, 1040.e1-4.

Kepert I.# , Fonseca J.#, Müller C., Milger K., Hochwind K., Kostric M., Fedoseeva M., Ohnmacht C., Dehmel S., Nathan P., Bartel S., Eickelberg O., Schloter M., Hartmann A., Schmitt-Kopplin P. and Krauss-Etschmann S. D-tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease. J Allergy Clin Immuol 2016, in press doi: 10.1016/j.jaci.2016.09.003

Ohnmacht, C.#, Park J.-H.#, Cording, S., Wing, J.B., Atarashi, K., Obata, Y., Gaboriau-Routhiau, V., Marques, R., Dulauroy, S., Fedoseeva, M., Busslinger, M., Cerf-Bensussan, N., Boneca, I.G., Voehringer, D., Hase, K., Honda, K., Sakaguchi, S. and G. Eberl. Symbiotic microbiota regulates type 2 immunity through RORγt+ T cells. Science 2015, 349(6251):989-93.

Ohnmacht, C.#, Schwartz, C.#, Panzer, M. Schiedewitz, I., Naumann, R. and D. Voehringer. Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 2010 33(3):364-74.

#co-first authorship.