Abstract
Toll-like receptors (TLRs) play a critical role in innate immune system responses to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). A growing body of evidence suggests that excessive TLR-mediated innate immune system activation can lead to neuronal damage and precipitate or perpetuate neurodegenerative diseases. Among TLR subtypes, both TLR2 and TLR9 have been implicated in neurodegenerative disorders with increased expression of these receptors in the central nervous system being associated with pro-inflammatory signaling and increased burdens of pathologic aggregated proteins. In the current study, we characterized the actions of a combined TLR2/TLR9 antagonist, NPT1220-312, on pro-inflammatory signaling and cytokine release in monocyte/macrophage-derived heterologous cells, human microglia, and murine and human whole blood. NPT1220-312 potently blocked TLR2- and TLR9-mediated release of inflammatory cytokines in monocyte/macrophage cells and in human microglia. NPT1220-312 also blocked TLR2-mediated activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome including IL-1β, IL-18, and apoptosis-associated speck-like protein containing a CARD (ASC) release to the culture medium of human differentiated macrophages. The ability of NPT1220-312 to inhibit TLR2 mediated pro-inflammatory release of chemokines and cytokines in situ was demonstrated using murine and human whole blood. Together, these findings suggest that blockade of TLR2 and TLR9 may reduce inappropriate production of pro-inflammatory cytokines and chemokines from peripheral and central immune cells and thus potentially provide therapeutic benefit in neuroinflammatory/neurodegenerative disorders.
Highlights
Agata Habas,1 Srinivasa Reddy Natala,2 Jon K
NPT1220-312 blocked TLR2-mediated activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome including IL-1β, IL-18, and apoptosis-associated speck-like protein containing a CARD (ASC) release to the culture medium of human differentiated macrophages. e ability of NPT1220-312 to inhibit TLR2 mediated pro-inflammatory release of chemokines and cytokines in situ was demonstrated using murine and human whole blood. These findings suggest that blockade of TLR2 and TLR9 may reduce inappropriate production of pro-inflammatory cytokines and chemokines from peripheral and central immune cells and potentially provide therapeutic benefit in neuroinflammatory/neurodegenerative disorders
Dysregulated immune responses, mediated in part by macrophages in the periphery and microglia in the central nervous system (CNS), can contribute to pathological conditions including autoimmune diseases and neurodegenerative disorders. us, pro-inflammatory actions of peripheral macrophages may contribute to the pathology of Guillain–Barresyndrome (GBS), an autoimmune disorder affecting the peripheral nervous system (PNS), while proinflammatory signaling arising, in part, from dysregulated microglia contributes to the progression of CNS neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) [2–8]
Summary
NPT1220-312 blocked TLR2-mediated activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome including IL-1β, IL-18, and apoptosis-associated speck-like protein containing a CARD (ASC) release to the culture medium of human differentiated macrophages. E priming step can be provided by microbial components or endogenous molecules, which can act via TLRs to increase pro-IL-1β and pro-IL-18 expression, while the activation step may be driven by aberrant aggregated host proteins such as α-synuclein or amyloid-β [19–26] In this manner, the twostep triggering of the NLRP3 inflammasome, involving priming by DAMPs acting, in part, through TLRs and activation by disease-associated aggregated host proteins provides a point of convergence for pathological processes that dysregulate immune responses and impair the degradation of disease-associated pathologic proteins
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