LPS and IL‐1 differentially activate mouse and human astrocytes: Role of CD14

Abstract

Treatment of cultures with toll-like receptor (TLR) ligands or cytokines has become a popular approach to investigate astrocyte neuroinflammatory responses and to simulate the neural environment in various CNS disorders. However, despite much effort, the mechanism of astrocyte activation such as their responses to the TLR ligands and IL-1 remain highly debated. We compared highly pure primary mouse and human astrocyte cultures in their ability to produce proinflammatory mediators (termed “A1”) and immunoregulatory mediators (termed “A2”) in response to LPS, poly IC and IL-1 stimulation. In human astrocytes, IL-1 induced both A1 and A2 responses, poly IC induced mostly A2, and LPS induced neither. In mouse astrocytes, LPS induced mostly an A1 predominant response, poly IC induced both A1 and A2, and IL-1 neither. In addition, mouse astrocytes produce abundant IL-1 protein while human astrocytes did not, despite robust IL-1 mRNA expression. Of the TLR4 receptor complex proteins, human astrocytes expressed TLR4 and MD2 but not CD14, while mouse astrocytes expressed all three. Mouse astrocyte CD14 (cell-associated and soluble) was potently upregulated by LPS. Silencing TLR4 or CD14 by siRNA suppressed LPS responses in mouse astrocytes. In vivo, astrocytes in LPS-injected mouse brains also expressed CD14. Our results show striking differences between human and mouse astrocytes in the use of TLR/IL-1R and subsequent downstream signaling and immune activation. IL-1 translational block in human astrocytes may be a built-in mechanism to prevent autocrine and paracrine cell activation and neuroinflammation. These results have important implications for translational research of human CNS diseases.

Microglial Heparan Sulfate Proteoglycans Facilitate the Cluster-of-Differentiation 14 (CD14)/Toll-like Receptor 4 (TLR4)-Dependent Inflammatory Response

“…Previous reports have offered conflicting conclusions regarding the expression of CD14 in astrocytes (42)(43)(44)(45). In particular, Tarassishin et al recently reported that mouse astrocytes express CD14 (46). Notably, however, Tarassishin et al passaged primary mouse astrocytes for 6-weeks prior to experiment.…”

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

“…It remains to be established whether this discrepancy is due to the particular experimental conditions employed or whether it reflects species differences. It is noteworthy that some significant functional differences have been described between mouse and human astrocytes (Oberheim et al, 2009;Tarassishin et al, 2014), and differences in gene expression between murine and human astrocytes might also be responsible for their distinct susceptibility to Fxn depletion. A recent analysis of the transcriptome of the prenatal human…”

Anti-inflammatory Effects of Propofol on Lipopolysaccharides-Treated Rat Hepatic Kupffer Cells

“…LPS, the most classic and ancient pathogenic factor, is the main pathogenic factor in Gram-negative bacteria [27]. Endotoxin shock by LPS can induce a series of Fig.…”