In its classical form, autophagy is an essential, homeostatic process by which cytoplasmic components are degraded in a double-membrane-bound autophagosome in response to starvation. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. The roles of autophagy bridge both the innate and adaptive immune systems and autophagic dysfunction is associated with inflammation, infection, neurodegeneration and cancer. In this review, we discuss the contribution of autophagy to inflammatory, infectious and neurodegenerative diseases, as well as cancer.

The activation of innate immune response is initiated by engagement of pattern-recognition receptors (PPRs), such as Toll-like receptors (TLRs). These receptors are expressed in peripheral leukocytes and in many cell types in the central nervous system (CNS). The expression of TLRs in CNS was mainly studied in astrocytes and microglial cells. However, new evidence indicates that these receptors may play an important role in neuronal homeostasis. The expression of TLRs in the CNS is variable and can be modulated by multiple factors, including pro-inflammatory molecules, which are elevated in neurodegenerative diseases and can increase the expression of TLRs in CNS cells. Moreover, activation of TLRs induces the release of pro-inflammatory cytokines. Therefore, TLRs have been shown to play a role in several aspects of neurodegenerative diseases. Here we will discuss results reported in the recent literature concerning the participation of TLRs in neurodegenerative diseases.

Autophagy is a fundamental cellular homeostatic mechanism, whereby cells autodigest parts of their cytoplasm for removal or turnover. Neurodegenerative disorders are associated with autophagy dysregulation, and drugs modulating autophagy have been successful in several animal models. Microglial cells are phagocytes in the central nervous system (CNS) that become activated in pathological conditions and determine the fate of other neural cells. Here, we studied the effects of autophagy on the production of pro-inflammatory molecules in microglial cells and their effects on neuronal cells. We observed that both trehalose and rapamycin activate autophagy in BV2 microglial cells and down-regulate the production of pro-inflammatory cytokines and nitric oxide (NO), in response to LPS and alpha-synuclein. Autophagy also modulated the phosphorylation of p38 and ERK1/2 MAPKs in BV2 cells, which was required for NO production. These actions of autophagy modified the impact of microglial activation on neuronal cells, leading to suppression of neurotoxicity. Our results demonstrate a novel role for autophagy in the regulation of microglial cell activation and pro-inflammatory molecule secretion, which may be important for the control of inflammatory responses in the CNS and neurotoxicity.