New mechanism activating the brain's immune system discovered
A team of researchers led by Silvia Di Angelantonio of the Vittorio Erspamer Department of Physiology and Pharmacology and the Nanotechnologies for neurosciences laboratory, coordinated by Giancarlo Ruocco of the Italian Institute of Technology (IIT), in collaboration with Columbia University, has published an article in the journal Cell Reports in which they have uncovered a new mechanism of activation of microglia, a type of cell that forms the first line of defence in the brain. This discovery could form the basis of new approaches to be used against neuropathic pain, often encountered following chemotherapy treatments in which microglia are involved.
Microglia are a type of cell present in the brain. They perform an immune function, i.e. they defend the nervous system from anything that might damage it, such as pathogens, tumour cells or inflammation. When no threats are present, microglia cells are present in the so-called 'non-activated' or 'surveillance' state characterised by a large number of ramifications that are used precisely to monitor the brain's environment in search of danger signals that, once found, will make the microglia acquire its 'activated state' by switching from a branched to a rounded shape, a conformation with which it can perform its defence function.
The team discovered the fundamental role that microtubules, which are key elements in shaping cells, play in converting from a non-activated to an activated state.
In the non-activated microglia, the microtubules line up in parallel, whereas in the activated microglia, they are arranged in a radial pattern, similar to a bicycle wheel. This reorganisation of the microtubules is crucial for activating the microglia; by blocking this process during their experiments, the team noticed that the microglia could no longer activate.
While non-activated and activated branched microglia are essential for brain health, microglia that remain stuck in the activated state contribute to brain inflammation and neurodegenerative diseases such as Parkinson's and Alzheimer's.
Furthermore, microglia are implicated in the development of neuropathic pain, often seen in patients treated with chemotherapy. That is because some chemotherapy drugs attack microtubules to destroy cancer cells. The problem is that these drugs often affect not only cancer cells but also healthy ones, thus generating pain.
"The future will be the development of new therapeutic approaches aimed at specifically modulating microtubule changes in microglia, without affecting other cells," concludes Silvia Di Angelantonio, study coordinator, "This is to prevent or counteract the pathological activation of microglia. We are only at the beginning of this pathway, but we are moving in this direction".
Microglia reactivity entails microtubule remodeling from acentrosomal to centrosomal arrays - Rosito M, Sanchini C, Gosti G, Moreno M, De Panfilis S, Giubettini M, Debellis D, Catalano F, Peruzzi G, Marotta R, Indrieri A, De Leonibus E, De Stefano ME, Ragozzino D, Ruocco G, Di Angelantonio S, Bartolini F. - Cell Reports 2023 Feb 28 42(2): 112104. DOI: https://doi.org/10.1016/j.celrep.2023.112104
Silvia Di Angelantonio
Vittorio Erspamer Department of Physiology and Pharmacology
Istituto Italiano di Tecnologia