Possible involvement of TLRs and hemichannels in stress-induced CNS dysfunction via mastocytes, and glia activation

Abstract

In the central nervous system (CNS), mastocytes and glial cells (microglia, astrocytes and oligodendrocytes) function as sensors of neuroinflammatory conditions, responding to stress triggers or becoming sensitized to subsequent proinflammatory challenges. The corticotropin-releasing hormone and glucocorticoids are critical players in stress-induced mastocyte degranulation and potentiation of glial inflammatory responses, respectively. Mastocytes and glial cells express different toll-like receptor (TLR) family members, and their activation via proinflammatory molecules can increase the expression of connexin hemichannels and pannexin channels in glial cells. These membrane pores are oligohexamers of the corresponding protein subunits located in the cell surface. They allow ATP release and Ca(2+) influx, which are two important elements of inflammation. Consequently, activated microglia and astrocytes release ATP and glutamate, affecting myelinization, neuronal development, and survival. Binding of ligands to TLRs induces a cascade of intracellular events leading to activation of several transcription factors that regulate the expression of many genes involved in inflammation. During pregnancy, the previous responses promoted by viral infections and other proinflammatory conditions are common and might predispose the offspring to develop psychiatric disorders and neurological diseases. Such disorders could eventually be potentiated by stress and might be part of the etiopathogenesis of CNS dysfunctions including autism spectrum disorders and schizophrenia.

Figure 1

Expression of toll-like receptors in microglia and their relationship with pannexin channels and P2X₇ receptors. Microglia express TLRs 1 to 9, and in this figure only, TLRs 3 and 4 are shown responding to pathogen-associated molecular patterns of virus (TLR3) and Gram negative bacteria (TLR4). TLR3 is expressed in endosomal membranes (and also in cell surface) and recognizes nucleic acids of virus (dsRNA) and poly (I:C). We propose that microglia under activation with TLR ligands increase the expression of Panx1 channels and connexin HCs and the activity of P2X₇ receptors.

Figure 2

Model of the involvement of mastocytes and microglia in neuroinflammatory responses and potentiation of their responses by stress. Stress increases the levels of CRH and glucocorticoids which are critical players in stress-induced mastocytes (M) degranulation and potentiation of glial inflammatory responses (sensibilization). Furthermore, perinatal infections, particularly those of viral etiology (poly (I:C)), are frequent and have been associated with diverse alterations of CNS. Mastocytes and microglia (MΦ) express toll-like receptor 3 (TLR3). Activated microglia and mastocytes increase the hemichannel activity in reactive astrocytes (A) and oligodendrocytes (O). Both activated microglia and astrocytes release ATP and glutamate that induce neurodegeneration through the activation of P2X₇ receptors and Panx1 channels in neurons (N) (neurodegeneration) (modified from Orellana et al., 2011) [125].