Abstract
ABSTRACT Type-I interferon (IFN-I) cytokines are produced by immune cells in response to microbial infections, cancer and autoimmune diseases, and subsequently, trigger cytoprotective and antiviral responses through the activation of IFN-I stimulated genes (ISGs). The ability of intestinal microbiota to modulate innate immune responses is well known, but the mechanisms underlying such responses remain elusive. Here we report that the intracellular sensors stimulator of IFN genes (STING) and mitochondrial antiviral signaling (MAVS) are essential for the production of IFN-I in response to lactic acid bacteria (LAB), common gut commensal bacteria with beneficial properties. Using human macrophage cells we show that LAB strains that potently activate the inflammatory transcription factor NF-κB are poor inducers of IFN-I and conversely, those triggering significant amounts of IFN-I fail to activate NF-κB. This IFN-I response is also observed in human primary macrophages, which modulate CD64 and CD40 upon challenge with IFN-I-inducing LAB. Mechanistically, IFN-I inducers interact more intimately with phagocytes as compared to NF-κB-inducers, and fail to activate IFN-I in the presence of phagocytosis inhibitors. These bacteria are then sensed intracellularly by the cytoplasmic sensors STING and, to a lesser extent, MAVS. Accordingly, macrophages deficient for STING showed dramatically reduced phosphorylation of TANK-binding kinase (TBK)-1 and IFN-I activation, which resulted in lower expression of ISGs. Our findings demonstrate a major role for intracellular sensing and STING in the production of IFN-I by beneficial bacteria and the existence of bacteria-specific immune signatures, which can be exploited to promote cytoprotective responses and prevent overreactive NF-κB-dependent inflammation in the gut.
Highlights
Type-I IFN (IFN-I) such as IFN-α and IFN-β are polypeptides produced by innate immune cells in response to infectious agents, viral pathogens[1]
Contrary to current dogma in which beneficial bacteria are mostly sensed by Toll-like receptors (TLRs), we show that IFN-I-inducing lactic acid bacteria (LAB) are sensed intracellularly via cytosolic nucleic acid sensors and that IFN-I production and I stimulated genes (ISGs) induction is dependent on stimulator of IFN genes (STING) and, to a lesser extent, mitochondrial antiviral signaling (MAVS)
A few studies have shown that LAB are capable of inducing the production of IFN-I in innate immune cells,[23,24,42,43] and when the mechanism has been reported, this has been linked with TLR2/3 recognition via endosomes.[23,24]
Summary
Type-I IFN (IFN-I) such as IFN-α and IFN-β are polypeptides produced by innate immune cells in response to infectious agents, viral pathogens[1]. The first described PRRs were Toll-like receptors (TLRs) and Nucleotidebinding oligomerization domain (NOD)-like intracellular receptors (NLRs) These PRRs activate an intracellular signaling cascade that converges on the proinflammatory transcription factor nuclear factor kappaB (NF-κB), which is crucial in regulating anti-microbial responses in the mucosa.[3] The production of IFN-I requires the additional and concomitant activation of IFN regulatory factors (IRFs), which can be achieved via the TLR adaptors myeloid differentiation primary response 88 (MyD88) and TIR domain-containing adapter-inducing IFN (TRIF).[4] More recently, the cytosolic molecules stimulator of interferon genes (STING) and mitochondrial antiviral signaling (MAVS) have been identified as potent IFN-I inducers in response to nucleic acids.[5] STING is an endoplasmic reticulum-localized transmembrane protein that becomes activated in the presence of cytosolic DNA and the production of 2‘,3‘cyclic GMP-AMP (cGAMP) by the cGAMP synthase
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