Neurotrophins as intercellular signaling molecules of the brain regulate select immune functions of microglia

Microglia are the resident immune cells of the brain, which become activated in response to diverse immune stimuli. Following activation, microglia signal to other central nervous system (CNS) cells by secreting a variety of cytokines. Under specific stimulatory conditions, microglia can also release a spectrum of cytotoxins, including reactive oxygen species (ROS), reactive nitrogen species (RNS), proteases, and other enzymes. Molecules secreted by microglia have specific functions in the neuroimmune response to pathogens and endogenous stimuli. They also contribute to the pathogenesis of neurodegenerative diseases. Neurotrophins (NTs) are proteins that support development, maturation and normal metabolic functions of neurons by interacting with neurotrophin receptors (NTRs) on these cells. Microglia also express several NTRs that signal in response to binding of NTs. These include tropomyosin receptor kinase (Trk)A, TrkB and p75NTR. Binding and activation of these receptors can alter the phenotype, metabolism, and other functions of microglia. We hypothesized that NTR ligands, such as the small molecule ligand LM11A-31 and the NT precursor pro-brain derived neurotrophic factor (proBDNF), bind p75NTR and modulate the immune functions of microglia. We studied the effects of NTR ligands on the following immune functions by using in vitro models of microglia: 1) secretion of cytotoxins and cytokines by lipopolysaccharide (LPS) plus interferon-γ stimulated human THP-1 monocytic cells; 2) release of ROS through the LPS-primed respiratory burst response of dimethyl sulfoxide-differentiated human HL-60 myelomonocytic cells; 3) secretion of nitric oxide by LPS-stimulated murine BV-2 microglia; and 4) phagocytic activity of BV-2 cells. LM11A-31 and proBDNF inhibited the respiratory burst response of differentiated HL-60 microglia-like cells but did not have a significant effect in most other cellular assays. Our data indicate that NTs could serve as intercellular signaling molecules of the CNS by regulating select immune functions of microglia, such as their production of ROS.