The overarching aim of our research is to understand how local immune responses are orchestrated to maintain tissue homeostasis under inflammatory conditions. Specifically, we want to understand the crosstalk of tissue resident immune cells and the surrounding tissue and to understand the underlying molecular mechanisms by which pro- and anti-inflammatory stimuli determine the outcome of local immune responses. Deficiencies in local immune regulation often lead to inflammation-associated diseases, such as fibrotic diseases, atherosclerosis or arthritis, as well as to auto-immune diseases or allergies. Thus, a better understanding of the fundamental mechanisms that regulate local immune responses are of central importance in order to find more efficient ways of treating such diseases.

In specific, we discovered that a crosstalk between the EGFR and TGFβ controls local immune responses. Based on a “biased agonism” of the EGFR, the low-affinity EGFR ligand Amphiregulin induces the local activation of TGFβ (Minutti et al., Immunity 2019). In this way, Amphiregulin enhances the suppressive capacity of regulatory T-cells, thereby critically contributing to the resolution of inflammation and tissue homeostasis. (Zaiss et al. Immunity 2013). TGFβ is expressed and stored in tissues in form of a latent complex. As a low-affinity EGFR ligand, Amphiregulin induces a tonic sustained signal which activates integrin-αV complexes on target cells and thus induces the local release of bio-active TGFβ. In this way, Amphiregulin contributes to local immune suppression and the differentiation of tissue residential stem cells, such as pericytes, and thus to tissue repair. (Minutti et al. Immunity 2019).

This rather unexpected concept of local immune regulation challenges and suggests the re-evaluation of several of our present perceptions with regard to inflammation, wound repair and tissue homeostasis; and, thus, also their implications for the development of tissue fibrosis, cancer and auto-immune diseases.

Combing experimental induced inflammation with an intravital microscopy-based approach in reporter mice, we are determining how local inflammation uses the EGFR / TGFβ crosstalk to impose a dynamic, spatio-temporal activity pattern of TGFβ that coordinates pathogen clearance with wound repair.

Using infection models, we are testing whether that at the site of infection, monocyte-derived HB-EGF expression prevails and suppresses TGFβ function and thus sustains efficient local immune response; while in the periphery, Amphiregulin prevails and induces TGFβ activation and thus the resolution of local inflammation; thereby facilitating wound repair by inducing the differentiation of tissue stem cells, as well as of myofibroblasts.

Via an enhanced collagen deposition, this enhanced myofibroblast differentiation contributes to wound healing, the encapsulation of the infection site – but can also leads to tissue fibrosis and loss of organ/lung function. To translate our findings into a clinical setting, we have been developing neutralizing antibodies and peptide-based inhibitors, which can specifically block the activity of either Amphiregulin or HB-EGF.

The Amphiregulin specific inhibitor prevents and reverts lung fibrosis in a chronic lung inflammation model (house dust mite extract) and a bleomycin model. We intend to develop these inhibitors further for the therapeutic application in lung transplant patients and in patients suffering from Idiopathic Pulmonary Fibrosis (IPF).

Also, we are testing HB-EGF neutralising antibodies in mouse models for its therapeutic efficacy, i.e. in treatment auto-immune diseases, such as rheumatoid arthritis. HB-EGF enhances the survival of T-effector cells and renders them resistant to regulatory T-cell. Hence, we predict that within inflamed joints HB-EGF specific inhibitors could mimic a situation observed following TNFα inhibitor treatment, which has been shown to enhance the suppressive capacity of regulatory T-cells in inflamed joints. Thus, HB-EGF specific inhibitors could potentially be utilized to supplement or substitute TNFα inhibitor treatments in their clinical use.

Discover more by visiting Professor Zaiss’s dedicated UKR page!

Here is a selection of the most important publications from the last few years:

Zaiss DM*, Pearce EJ, Artis D, McKenzie AN, & Klose CS* (2024) Cooperation of ILC2s and Th2 cells in the expulsion of intestinal helminth parasites. Nat Rev Immunol. 24:294-302.

du Halgouet A, Darbois A, Alkobtawi M, Mestdagh M, Alphonse A, Premel V, Yvorra T, Colombeau L, Rodriguez R, Zaiss D, El Morr Y, Bugaut H, Legoux F, Perrin L, Aractingi S, Golub R, Lantz O, Salou M. (2023) Role of MR1-driven signals and amphiregulin on the recruitment and repair function of MAIT cells during skin wound healing. Immunity 56:78-92.

Minutti CM, Modak RV, Macdonald F, Li F, Smyth DJ, Dorward DA, Blair N, Husovsky C, Muir A, Giampazolias E, Dobie R, Maizels RM, Kendall TJ, Griggs DW, Kopf M, Henderson NC, Zaiss DM*. (2019) A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation. Immunity 50:645-654

Zaiss DM* & Coffer PJ* (2018) Forkhead box transcription factors as context-dependent regulators of immune homeostasis. Nat Rev Immunol. 18: 703-15

Minutti CM, Blair N, Schwartz C, Drube S, Kamradt T, Sibilia M, Sijts AJ, Fallon PG, Maizels RM, Zaiss DM*. (2017) Epidermal growth factor receptor expression licenses Th2 cells to function in a TCR-independent way. Immunity 47:710-722

Minutti CM, Jackson-Jones LH, García-Fojeda B, Logan N, Rinqvist E, Guillamat-Prats R, Artigas A, Stamme C, Chroneos ZC, Zaiss DM, Casals C*, Allen JE.* (2017) Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver. Science 356: 1076-8

Zaiss DM*, Gause WC*, Osborne LC, Artis D* (2015) Emerging functions of Amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42: 216-26

Zaiss DM*., van Loosdregt J., Gorlani A., Bekker CJ., Gröne A., Sibilia M., van Bergen en Henegouwen PM., Roovers RC, Coffer PJ, Sijts AJ. (2013) Amphiregulin enhances regulatory T cell suppressive function via the epidermal growth factor receptor. Immunity 38: 275-28

van Loosdregt J., Fleskens V., Tiemessen MM., van Boxtel R., Mokry M., Meerding J., Pals CE., Kurek D., Baert MR., Delemarre EM., Gröne A., Sijts AJ., Maurice MM., van Es JH., ten Berge D., Staal FJ., Zaiss DM., Prakken BJ., and Coffer PJ.* (2013) Canonical Wnt signaling negatively modulates T regulatory cell function. Immunity 39: 298-310

van Loosdregt J., Fleskens V., Fu J., Brenkman AB., Bekker CJ., Pals CE., Meerding J., Berkers CR., Barbi J., Gröne A., Sijts AJ., Maurice MM., Kalkhoven E., Prakken BJ., Ovaa H., Pan F., Zaiss DM., and Coffer PJ.* (2013) USP7/HAUSP mediated stabilization of FoxP3 increases Treg suppressive capacity. Immunity 39: 259-271

Zaiss DM, Yang L, Shah PR, Kobie JJ, Urban JF, Mosmann TR.* (2006) Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science 314:1746.

Schubert D, Schmidt M, Zaiss D, Jungblut P, Kamradt T.* (2002) Autoantibodies against GPI and creatine kinase in rheumatoid arthritis. Nature Immunol. 3: 411

Visit the complete list of Prof. Zaiss’s publications on PubMed and Google Scholar:

https://pubmed.ncbi.nlm.nih.gov/?term=Zaiss+D.&sort=pubdate

https://scholar.google.com/citations?user=wunOhNMAAAAJ&hl=en&oi=ao