TGFβ regulates persistent neuroinflammation by controlling Th1 polarization and ROS production via monocyte-derived dendritic cells.

Intracerebral levels of Transforming Growth Factor beta (TGFβ) rise rapidly during the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis (MS). We addressed the role of TGFβ responsiveness in EAE by targeting the TGFβ receptor in myeloid cells, determining that Tgfbr2 was specifically targeted in monocyte-derived dendritic cells (moDCs) but not in CNS resident microglia by using bone-marrow chimeric mice. TGFβ responsiveness in moDCs was necessary for the remission phase since LysM(Cre) Tgfbr2(fl/fl) mice developed a chronic form of EAE characterized by severe demyelination and extensive infiltration of activated moDCs in the CNS.

Inhibition of meningitis-associated neutrophil apoptosis by TNF-α depends on functional PI3-kinase in monocytes.

In bacterial meningitis, neutrophils cope with bacterial infection but also lead to tissue damage. The balance of beneficial and harmful effects may depend on the lifespan of the neutrophils in the CNS. Here, we show that CSF of patients with meningococcal meningitis contains a neutrophil apoptosis-inhibiting capacity that correlates with TNF-α content.

Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet.

Aims/hypothesis: Inflammation contributes to both insulin resistance and pancreatic beta cell failure in human type 2 diabetes. Toll-like receptors (TLRs) are highly conserved pattern recognition receptors that coordinate the innate inflammatory response to numerous substances, including NEFAs. Here we investigated a potential contribution of TLR2 to the metabolic dysregulation induced by high-fat diet (HFD) feeding in mice.

Bacterial meningitis: the role of transforming growth factor-Beta in innate immunity and secondary brain damage.

Project 6 of the NCCR 'Neural Plasticity and Repair' focuses on mechanisms of immunity and tissue damage in autoimmune and infectious diseases of the central nervous system (CNS). In one of the subprojects, the influence of transforming growth factor-beta (TGF-beta) on the immune reactivity of the CNS was investigated. In mice with Streptococcus pneumoniae-induced meningitis, a deletion of TGF-beta receptor II on leukocytes is found to enhance recruitment of neutrophils to the site of infection and to promote bacterial clearance.

TGFbeta receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis.

In bacterial meningitis, chemokines lead to recruitment of polymorphonuclear leucocytes (PMN) into the CNS. At the site of infection in the subarachnoid space, PMN release reactive oxygen species, reactive nitrogen intermediates (RNI) and interleukin-1beta (IL-1beta). Although these immune factors assist in clearance of bacteria, they also result in neuronal injury associated with meningitis.