Type I Interferons Function as Autocrine and Paracrine Factors to Induce Autotaxin in Response to TLR Activation

Abstract

Lysophosphatidic acid (LPA) is an important phospholipid mediator in inflammation and immunity. However, the mechanism of LPA regulation during inflammatory response is largely unknown. Autotaxin (ATX) is the key enzyme to produce extracellular LPA from lysophosphatidylcholine (LPC). In this study, we found that ATX was induced in monocytic THP-1 cells by TLR4 ligand lipopolysaccharide (LPS), TLR9 ligand CpG oligonucleotide, and TLR3 ligand poly(I:C), respectively. The ATX induction by TLR ligand was abolished by the neutralizing antibody against IFN-β or the knockdown of IFNAR1, indicating that type I IFN autocrine loop is responsible for the ATX induction upon TLR activation. Both IFN-β and IFN-α were able to induce ATX expression via the JAK-STAT and PI3K-AKT pathways but with different time-dependent manners. The ATX induction by IFN-β was dramatically enhanced by IFN-γ, which had no significant effect on ATX expression alone, suggesting a synergy effect between type I and type II IFNs in ATX induction. Extracellular LPA levels were significantly increased when THP-1 cells were treated with IFN-α/β or TLR ligands. In addition, the type I IFN-mediated ATX induction was identified in human monocyte-derived dendritic cells (moDCs) stimulated with LPS or poly(I:C), and IFN-α/β could induce ATX expression in human peripheral blood mononuclear cells (PBMCs) and monocytes isolated form blood samples. These results suggest that, in response to TLR activation, ATX is induced through a type I INF autocrine-paracrine loop to enhance LPA generation.

Genetic deletion of Autotaxin from CD11b+ cells decreases the severity of experimental autoimmune encephalomyelitis

“…LPS-mediated TLR activation of monocytic THP-1 cells was also reported to lead to ATX production [39]. Moreover, it was recently reported that LPA stimulates the expression of F4/80, a well-known macrophage activation marker [4], in bone marrowderived and splenic monocytic (CD11b + ) cells [40].…”

Neonatal detection of Aicardi Goutières Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots

“…Thus it is presumed that the finding of elevated C26:0 Lyso-PC in AGS subjects represents a false positive for X-ALD screening. We speculate that elevated C26:0 Lyso-PC, and perhaps elevations in other phosphatidylcholines, may be a marker of an undefined downstream inflammatory pathway in AGS pathophysiology 31; 32 .…”

Nano-based approach to combat emerging viral (NIPAH virus) infection

“…26,27 Song et al describe that IFN α/β can act as both autocrine and paracrine signaling molecule, where IFN α and IFN β are producers. 28 Therefore it could be said that inhibition of IFN α/β synthesis may severely affect both autocrine and paracrine activity, which may further lead to impaired immune response (Barth et al 2016). 29 The cellular and molecular changes during and post NiV infection starting right from NiV attachment and invasive pathogenesis leading to multiple organ failure have been explained in the Figures 1, 2, and 3.…”