Glial toll-like receptor signaling in central nervous system infection and autoimmunity

Abstract

Innate immunity in the CNS depends primarily on the functions of glial cells, astrocytes and microglia, which are important for the early control of pathogen replication and direct the recruitment and activation of cells of the adaptive immune system required for pathogen clearance. Efficient immune responses are required for clearance of an invading pathogen, but dysregulation of a proinflammatory response in the CNS could lead to the development of autoimmunity. This review summarizes the activation of Toll-like receptors (TLRs) expressed on glial cells and the functional outcome of these interactions for CNS health and disease which depends on a delicate balance of the protective and toxic effects of molecules induced in the CNS following TLR ligation.

Evaluating the role of Toll-like receptors in diseases of the central nervous system

“…In vitro studies showed that heat inactivated GBS and a secreted factor 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 30 from GBS induced neuronal apoptosis via the TLR2 and MyD88 dependent production of NO from microglia. This observation is indicative of a mode of neurodegeneration that may contribute to the disease process of GBS meningitis in neonates [17]. Furthermore GBS can trigger microglial apoptosis in a pathway dependent upon TLR2 and caspase 8 [101].…”

“…In contrast human neurons only express TLR3 [14], while Page 7 of 62 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 7 both mouse and human microglia express mRNA for TLR1-9 [15] [16] (Table 1). The expression of TLR3 is particularly interesting as it is highly expressed in both murine and human astrocytes and highly expressed in the resting CNS [17] suggesting that it may have vital immune or homeostatic roles in the brain.…”

“…For example microglia expressing TLRs are located at regions exposed to the circulation such as the circumventricular organs, meninges and choroid plexus [17,18]. TLR expression in the CNS is enhanced by bacterial and viral infection in order to initiate an inflammatory response [17].…”

“…For example microglia expressing TLRs are located at regions exposed to the circulation such as the circumventricular organs, meninges and choroid plexus [17,18]. TLR expression in the CNS is enhanced by bacterial and viral infection in order to initiate an inflammatory response [17]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 26 microglia and astrocytes with either TLR ligands or pathogens results in the production of a variety of inflammatory mediators [17].…”

JAK-STAT Lodges in Multiple Sclerosis: Pathophysiology and Therapeutic Approach Overview

“…Moreover, IL-6 promotes Th17 and B cell differentiation [60], whereas, IFN-γ induced JAK1/2-STAT1 signaling effect which was observed in classically-activated macrophages [61] IL-27 JAK1/STAT-3 Treg IL-10, TGFRβ1 [34] JAK/STAT4 and NF-κB play important role in the pathways involved in pro-inflammatory processes [54]. Activation of the NF-κB transcription factor results in production of proinflammatory cytokines, nitric oxide (NO) and secretion of chemokines by macrophages, whereas on Dendritic cells there is increase expression of CD83, CD86, and CD40, as well as MHC class II [64] which could be important in MS pathogenesis.…”