Center for Molecular Medicine Cologne

Langmann, Thomas - B 05

Microglia modulation as target for diabetic retinopathy


Driven by rising incidence in Diabetes mellitus, Diabetic retinopathy (DR) has grown in medical significance and is now a global public health concern. Delineating the precise contribution of microglia inflammatory responses in DR pathogenesis may indicate new approaches for therapeutic intervention since compelling evidence suggests that inflammatory responses play a key role in the development and progression of DR. 

Diabetic Retinopathy (DR) is a complication of diabetes and is a major cause of irreversible blindness among the working age population. DR has traditionally been regarded as a microvasculature disease, however mounting evidence from human patients and mouse models show that inflammation contributes significantly to the pathogenesis of DR. Inflammatory responses during retinal pathophysiology are orchestrated primarily by microglia cells, which constitute the resident immune cell population. However, the exact contribution of microglia to DR pathophysiology has remained unclear, largely due to lack of adequate DR animal models that mimic the human disease.

Recently, it was demonstrated in two separate innovative mouse models that inhibition of platelet-derived growth factor (PDGF)-B/PDGF receptor beta (PDGFRβ) signaling during development of retinal vessels is sufficient to reproduce characteristic features of DR in adult mice. These novel mice models provide an essential tool for studying DR and development of novel therapies. Therefore, in this project, we propose to perform an in-depth analysis of retinal microglia at different stages of DR.

We also aim to fully characterize microglial roles in DR using i) microglial ablation with a colony stimulating factor 1 receptor (CSF1-R) antagonist ii) modulation of microglia reactivity with a second generation tetracycline, minocycline  which we and others have shown to be a potent modulator of retinal microgliosis. This study will not only improve our understanding of microglia in DR pathogenesis but may also demonstrate microglia as potential therapeutic targets.

Our Aims

  1. Understand the contribution of retinal microglia to DR pathogenesis at different stages of the disease
  2. To determine whether modulation of microglial reactivity or microglia ablation ameliorates DR pathology

Previous Work

We and others have over the years provided compelling evidence using animal models and in-situ analysis of human tissue that when retinal homeostasis is compromised by noxious stimuli such as high-intensity light or genetic mutations, reactive microglia actively contribute to the demise of retinal neurons (Dannhausen et al., 2018; Lückoff et al., 2016, 2017; Scholz et al., 2015).

Consistently, we and others have shown that modulating microglia reactivity is sufficient to significantly attenuate photoreceptor cell death and preserve retinal integrity (Dannhausen et al., 2018; Lückoff et al., 2016; Scholz et al., 2015; Wang et al., 2014), suggesting that immune based therapies that counter excessive microglia-mediated neuroinflammatory responses may have a central role in the future clinical management of retinal disorders.

This concept of immune based therapies in the treatment of DR is especially attractive since 40-50% of patients treated with anti-VEGF agents to inhibit pathological neoangiogenesis fail to respond to therapy. Notably, we have previously shown that reactive mononuclear phagocytes in the retina are a source of pro-angiogenic cytokines and growth factors such as VEGF and placental growth factor (PGF) (Figure 1) (Balser et al., 2019) and that modulating microglial reactivity with immunomodulatory agents such as interferon beta (IFN-β) significantly reduces laser-induced choroidal neovascularization (CNV) in mice (Lückoff et al., 2016).

Figure 1

These findings imply that pharmacological strategies to target inflammation-mediated angiogenesis may help to increase efficacy and reduce non-responders in the treatment of diabetic DME, an important complication of DR that contributes greatly to vision loss. Therefore in the current study, we aim to conclusively determine microglial contributions at different stages of DR pathology using innovative ablation animal feeds containing a selective colony stimulating factor 1 receptor (CSF1R) inhibitor which transiently eliminates microglia within 1 week of oral feeding (Elmore et al., 2014; Okunuki et al., 2019).

We also aim to explore the role of microglia-mediated inflammatory responses in DR pathogenesis using immunomodulatory interventions with the tetracycline Minocycline, which we have previously shown to potently counter-regulate microgliosis and protect against light-induced retinal damage in mice (Figure 2). Once completed, this study will not only improve our understanding of microglial mechanisms to the onset and progression of DR, but might as well demonstrate microglia as potential therapeutic targets for the treatment of DR.

Figure 2
  • Balser, C., Wolf, A., Herb, M., and Langmann, T. (2019). Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina. J. Neuroinflammation16, 26.
  • Dannhausen, K., Möhle, C., and Langmann, T. (2018). Immunomodulation with minocycline rescues retinal degeneration in juvenile neuronal ceroid lipofuscinosis mice highly susceptible to light damage. Dis. Model. Mech. 11, dmm033597.
  • Elmore, M.R.P., Najafi, A.R., Koike, M.A., Dagher, N.N., Spangenberg, E.E., Rice, R.A., Kitazawa, M., Matusow, B., Nguyen, H., West, B.L., et al. (2014). Colony-Stimulating Factor 1 Receptor Signaling Is Necessary for Microglia Viability, Unmasking a Microglia Progenitor Cell in the Adult Brain. Neuron 82, 380–397.
  • Lückoff, A., Caramoy, A., Scholz, R., Prinz, M., Kalinke, U., and Langmann, T. (2016). Interferon‐beta signaling in retinal mononuclear phagocytes attenuates pathological neovascularization. EMBO Mol. Med.8, 670–678.
  • Lückoff, A., Scholz, R., Sennlaub, F., Xu, H., and Langmann, T. (2017). Comprehensive analysis of mouse retinal mononuclear phagocytes. Nat. Protoc.12, 1136–1150.
  • Okunuki, Y., Mukai, R., Nakao, T., Tabor, S.J., Butovsky, O., Dana, R., Ksander, B.R., and Connor, K.M. (2019). Retinal microglia initiate neuroinflammation in ocular autoimmunity. Proc. Natl. Acad. Sci. U. S. A. 116, 9989–9998.
  • Scholz, R., Caramoy, A., Bhuckory, M.B., Rashid, K., Chen, M., Xu, H., Grimm, C., and Langmann, T. (2015). Targeting translocator protein (18 kDa) (TSPO) dampens pro-inflammatory microglia reactivity in the retina and protects from degeneration. J. Neuroinflammation12.
  • Wang, M., Wang, X., Zhao, L., Ma, W., Rodriguez, I.R., Fariss, R.N., and Wong, W.T. (2014). Macroglia-microglia interactions via TSPO signaling regulates microglial activation in the mouse retina. J. Neurosci.34, 3793–3806.
  • Khan AS, Wolf A, and Langmann T (2021). The AhR ligand 2, 2'-aminophenyl indole (2AI) regulates microglia homeostasis and reduces pro-inflammatory signaling. Biochem Biophys Res Commun579, 15-21. doi:10.1016/j.bbrc.2021.09.054.
  • Uemura A, Fruttiger M, D’Amore PA, De Falco S, Joussen AM, Sennlaub F, Brunck LR, Johnson KT, Lambrou GN, Rottenhouse KD, Langmann T (2021). VEGFR1 signaling in retinal angiogenesis and microinflammation. Prog Retin Eye Res, 84:100954
  • Behnke V, and Langmann T (2020). IFN-beta signaling dampens microglia reactivity but does not prevent from light-induced retinal degeneration. Biochemistry and biophysics reports 24, 100866.
  • Khan AS, and Langmann T (2020). Indole-3-carbinol regulates microglia homeostasis and protects the retina from degeneration. Journal of neuroinflammation 17, 327.
  • Kinuthia UM, Wolf A, Langmann T (2020). Microglia and Inflammatory Responses in diabetic Retinopathy. Front Immunol 11:564077
  • Rashid K, Verhoyen M, Taiwo M, and Langmann T (2020). Translocator protein (18 kDa) (TSPO) ligands activate Nrf2 signaling and attenuate inflammatory responses and oxidative stress in human retinal pigment epithelial cells. Biochem Biophys Res Commun 10.1016/j.bbrc.2020.05.114.
  • Wolf A, Herb M, Schramm M, and Langmann T (2020). The TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye. Nat Commun 11, 2709.
  • Behnke V, Wolf A, and Langmann T (2020). The role of lymphocytes and phagocytes in age-related macular degeneration (AMD). Cell Mol Life Sci 77, 781-8.
Prof. Dr. Thomas Langmann CMMC Cologne
Prof. Dr. Thomas Langmann

Clinic of General Ophthalmology | Lab. for Experimental Immunology of the Eye

CMMC - PI - B 05

+49 221 478 7324

+49 221 478 32400

Clinic of General Ophthalmology | Lab. for Experimental Immunology of the Eye

Joseph-Stelzmann-Str. 9

50931 Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Thomas Langmann

Link to PubMed

Group Members

Verena Behnke
Amir Khan
Nils Laudenberg
Eva Scheiffert
Mona Tabel
Anja Volkmann
Anne Wolf