Roberta Brambilla, Ph.D. Publishes Manuscript in Cell Reports

Roberta Brambilla, Ph.D., Assistant Professor, Departments of Neurological Surgery and The Miami Project, and colleagues publish Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis in the journal Cell Reports. For several years, Dr. Brambilla and her associates have been interested in understanding the biological functions of the soluble and membrane forms of tumor necrosis factor (TNF), a cytokine involved in numerous physiological and pathological processes, including immune function and inflammation. They demonstrated that soluble TNF is detrimental in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), whereas membrane TNF is protective (Brambilla et al., Brain 2011).

TNFR2 is the primary signaling partner of membrane TNF and is highly expressed in microglia and monocytes/macrophages, two myeloid cell populations which play crucial roles in MS/EAE pathophysiology. In this context, Dr. Brambilla undertook the present study with the goal of systematically dissecting the functions of TNFR2 in microglia and monocytes/macrophages, as well as their contribution to EAE etiopathology.

What the researchers uncovered is a dichotomy of functions for microglial versus monocyte/macrophagic TNFR2: TNFR2 in microglia is protective and provides signals to contain neuroinflammation, whereas TNFR2 in monocyte/macrophages is detrimental by driving immune activation and EAE initiation.

Dr. Brambilla and her team demonstrated that TNFR2 directly regulates microglial phagocytosis, providing the first evidence that TNF signaling controls this process. Their work also highlights the complexity of TNF function in neuroimmune disease. Not only does TNF have opposite roles whether in soluble or transmembrane form, with soluble TNF being proinflammatory and membrane TNF protective, but so does its receptor TNFR2, depending on its location in central or peripheral myeloid cells.

Finally, in identifying TNFR2 in microglia as a protective signal in demyelinating disease, Dr. Brambilla proposes the idea that molecules activating TNFR2 in the CNS, either alone or in combination with selective soluble TNF blockers to enhance the availability of membrane TNF, could be explored in the therapy of multiple sclerosis and, potentially, of other neurodegenerative diseases, including spinal cord injury. Therefore, this study has significant translational implications. To read full paper click here.