Uncovering the molecular mechanisms of TGFβ-signalling-mediated regulation of postnatal microglia maturation and activation

• Applicant: Professor Dr. Björn Spittau
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278546913

• Final Report Year: 2025

Final Report Abstract

Microglia, the resident immune cells of the central nervous system (CNS), play crucial roles in brain homeostasis, neuroinflammation, and neurodegenerative diseases. During the recent funding periods we have identified microglia as highly responsive to TGFβ1 (Transforming Growth Factor Beta), which regulates their homeostasis, immune responses, and neuroprotective functions dependent on Tgfbr2 (TGFβ Receptor Type 2) and Smad4, both of which being crucial for mediating TGFβ1 effects on microglia. Early postnatal deletion of Tgfbr2 or Smad4 in microglia results in loss of expression of homeostatic markers such as Tmem119, P2ry12, Csf1r, Gpr34, Olfml3, Hexb or Sall1. Moreover, increased expression of reactive microglia markers such as Apoe, Spp1, Cst7, Nos2, Lpl or Gpnmb have been observed in Smad4-deficient microglia and are accompanied by massive changes in chromatin accessibility as demonstrated using ATAC-seq. Lack of Smad4 in microglia further impairs postnatal CNS development and triggers astrocyte activation, impairs myelination and results in an age-dependent decline of cortical GABAergic inhibitory neurons accompanied by a hyperactive motor phenotype associated by decreased motor coordination. Interestingly, Tgfbr2-deficient microglia tend to recover over time and display normal marker expression whereas Smad4-deficient microglia display stable phenotypes. We were able to demonstrate that BMPs (bone morphogenetic proteins) – as members of the TGFβ superfamily - are able to activate TGFβ signalling in microglia and, thus, compensate the lack of TGFβ1 responsiveness after deletion of Tgfbr2. Noteworthy, SMAD4 is the common intracellular downstream mediator for TGFβ1, Activin and BMP signalling further underlining the importance of Smad4 for microglial homeostasis. Taken together, Tgfbr2 and Smad4 are essential for maintaining microglial homeostasis and preventing excessive neuroinflammation. However, its dysregulation might contribute to neurodegenerative diseases by impairing microglial responses. The successful establishment and characterisation of Tgfbr2 and Smad4 microglia-specific mutant mice has provided the basis for further studies using mouse models for neurodegenerative diseases in order to lead to therapeutic strategies targeting microglial TGFβ signalling.

Publications

• Aging Microglia—Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases. Frontiers in Aging Neuroscience, 9.
  Spittau, Björn
  
• Microglia-Specific Expression of Olfml3 Is Directly Regulated by Transforming Growth Factor β1-Induced Smad2 Signaling. Frontiers in Immunology, 9.
  Neidert, Nicolas; von Ehr, Alexander; Zöller, Tanja & Spittau, Björn
  
• Postnatal maturation of microglia is associated with alternative activation and activated TGFβ signaling. Glia, 66(8), 1695-1708.
  Attaai, Abdelraheim; Neidert, Nicolas; von Ehr, Alexander; Potru, Phani Sankar; Zöller, Tanja & Spittau, Björn
  
• Silencing of TGFβ signalling in microglia results in impaired homeostasis. Nature Communications, 9(1).
  Zöller, Tanja; Schneider, Artur; Kleimeyer, Christian; Masuda, Takahiro; Potru, Phani Sankar; Pfeifer, Dietmar; Blank, Thomas; Prinz, Marco & Spittau, Björn
  
• Inhibition of Microglial TGFβ Signaling Increases Expression of Mrc1. Frontiers in Cellular Neuroscience, 14.
  von Ehr, Alexander; Attaai, Abdelraheim; Neidert, Nicolas; Potru, Phani Sankar; Ruß, Tamara; Zöller, Tanja & Spittau, Björn
  
• The Role of TGFβ Signaling in Microglia Maturation and Activation. Trends in Immunology, 41(9), 836-848.
  Spittau, Björn; Dokalis, Nikolaos & Prinz, Marco
  
• Characterization of the Leucocyte Immunoglobulin-like Receptor B4 (Lilrb4) Expression in Microglia. Biology, 10(12), 1300.
  Kretzschmar, Felix; Piecha, Robin; Jahn, Jannik; Potru, Phani Sankar & Spittau, Björn
  
• Microglial CD74 Expression Is Regulated by TGFβ Signaling. International Journal of Molecular Sciences, 23(18), 10247.
  Jahn, Jannik; Bollensdorf, Antonia; Kalischer, Christopher; Piecha, Robin; Weiß-Müller, Jana; Potru, Phani Sankar; Ruß, Tamara & Spittau, Björn
  
• A Custom Panel for Profiling Microglia Gene Expression. Cells, 13(7), 630.
  Potru, Phani Sankar; Vidovic, Natascha; Wiemann, Susanne; Russ, Tamara; Trautmann, Marcel & Spittau, Björn
  
• Microglial Transforming Growth Factor-β Signaling in Alzheimer’s Disease. International Journal of Molecular Sciences, 25(6), 3090.
  Vidovic, Natascha & Spittau, Björn