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Within the central nervous system the traditional role of microglia has been in brain infection and disease, phagocytosing debris and secreting factors to modify disease progression. More recently, microglia have been found to be important for normal brain development, circuit refinement, and synaptic plasticity in ways that were previously unsuspected. Hence, the brain innate immune system appears to be key in all situations, ranging from physiology to pathology. This unique feature of microglia is established by the wide array of receptors it is equipped with to sense molecular patterns. This includes receptors to most if not all neurotransmitters, neuromodulators and purines. We here review novel, yet extensive literature on a new class of microglia modulators, namely bioactive fatty acids. These lipids are issued from metabolism of nutrients and can cross the blood brain barrier to reach the CNS. They appear to be direct modulators of microglial activity, triggering/inhibiting inflammatory processes or enhancing/inhibiting the ability of these cells to respond to hazardous agents.