25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages.

Macrophages are critical to turn noninflamed "cold tumors" into inflamed "hot tumors". Emerging evidence indicates abnormal cholesterol metabolites in the tumor microenvironment (TME) with unclear function. Here, we uncovered the inducible expression of cholesterol-25-hydroxylase (Ch25h) by interleukin-4 (IL-4) and interleukin-13 (IL-13) via the transcription factor STAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmed that CH25Hhi subsets were enriched in immunosuppressive macrophage subsets and correlated to lower survival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressive function to enhance infiltrating T cell numbers and activation, which synergized with anti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HC competed with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leading to AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564 to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as an immunometabolic checkpoint, which manipulates macrophage fate to reshape CD8+ T cell surveillance and anti-tumor response.

DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response.

Detection of cytosolic nucleic acids by pattern recognition receptors, including STING and RIG-I, leads to the activation of multiple signalling pathways that culminate in the production of type I interferons (IFNs) which are vital for host survival during virus infection. In addition to protective immune modulatory functions, type I IFNs are also associated with autoimmune diseases. Hence, it is important to elucidate the mechanisms that govern their expression. In this study, we identified a critical regulatory function of the DUSP4 phosphatase in innate immune signalling. We found that DUSP4 regulates the activation of TBK1 and ERK1/2 in a signalling complex containing DUSP4, TBK1, ERK1/2 and IRF3 to regulate the production of type I IFNs. Mice deficient in DUSP4 were more resistant to infections by both RNA and DNA viruses but more susceptible to malaria parasites. Therefore, our study establishes DUSP4 as a regulator of nucleic acid sensor signalling and sheds light on an important facet of the type I IFN regulatory system.

Antioxidant Nanoparticles Restore Cisplatin-Induced Male Fertility Defects by Promoting MDC1-53bp1-Associated Non-Homologous DNA Repair Mechanism and Sperm Intracellular Calcium Influx.

Introduction: Cisplatin, a commonly used anticancer compound, exhibits severe off-target organ toxicity. Due to its wide application in cancer treatment, the reduction of its damage to normal tissue is an imminent clinical need. Cisplatin-induced testicular oxidative stress and damage lead to male sub- or infertility. Despite earlier studies showing that the natural polyphenol extracts honokiol serve as the free radical scavenger that reduces the accumulation of intracellular free radicals, whether honokiol exhibits direct effects on the testis and sperm is unclear. Thus, the aim of the current study is to investigate the direct effects of honokiol on testicular recovery and sperm physiology. Methods: We encapsulated this polyphenol antioxidation compound into liposome-based nanoparticles (nHNK) and gave intraperitoneally to mice at a dosage of 5 mg/kg body mass every other day for consecutive 6 weeks. Results: We showed that nHNK promotes MDC1-53bp1-associated non-homologous DNA double-strand break repair signaling pathway that minimizes cisplatin-induced DNA damage. This positive effect restores spermatogenesis and allows the restructuring of the multi-spermatogenic layers in the testis. By reducing mitochondrial oxidative damage, nHNK also protects sperm mitochondrial structure and maintains both testicular and sperm ATP production. By a yet-to-identify mechanism, nHNK restores sperm calcium influx at the sperm midpiece and tail, which is essential for sperm hypermotility and their interaction with the oocyte. Discussion: Taken together, the nanoparticulated antioxidant counteracts cisplatin-induced male fertility defects and benefits patients undertaking cisplatin-based chemotherapy. These data may allow the reintroduction of cisplatin for systemic applications in patients at clinics with reduced testicular toxicity.

Sensory gamma entrainment: Impact on amyloid protein and therapeutic mechanism.

The deposition of amyloid ß peptide (Aß) is one of the main pathological features of AD. The much-talked sensory gamma entrainment may be a new treatment for Aß load. Here we reviewed the generation and clearance pathways of Aß, aberrant gamma oscillation in AD, and the therapeutic effect of sensory gamma entrainment on AD. In addition, we discuss these results based on stimulus parameters and possible potential mechanisms. This provides the support for sensory gamma entrainment targeting Aß to improve AD.

Effect of 40 Hz light flicker on behaviors of adult C57BL/6J mice.

40 Hz light flicker can activate multiple brain regions of wild-type mice. However, there are no systematic studies on the behavioral effects of 40 Hz light flicker on wild-type mice. Adult wild-type C57BL/6J mice were treated with 40 Hz light flicker (200 lx, 40 Hz, 1 h/day for 3 weeks) to evaluate its effects on several behaviors, including mood, locomotor activity, memory, social interaction, mechanical pain, and sense of smell. In the open field test, the elevated zero-maze test, forced swimming test, and tail suspension test, 40 Hz mice showed no anxiety and depression-like behaviors. In the rotarod test, no differences were found between the anti-fatigue ability and motor coordination ability. In memory-related tests, 40 Hz mice showed the short-term cognitive enhancement in the novel object recognition test. Interestingly, 40 Hz mice showed no enhanced the long-term memory performance in the contextual fear conditioning test, and tone-cued fear conditioning test. Besides, 40 Hz mice increased their exploration of social cues that were unfamiliar to them and differed significantly from their own experiences. In terms of sensory abilities, 40 Hz mice had unchanged pain sensitivity in the von Frey fiber test and significant enhancement in the olfactory ability in the food-seeking test. In conclusion, this 40 Hz light stimulation paradigm has high safety and can improve the specific behavioral ability, which provides a theoretical basis for the future use of 40 Hz light flicker as a disease prevention or treatment method.

Olfactory Evaluation in Alzheimer's Disease Model Mice.

Olfactory dysfunction is considered a pre-cognitive biomarker of Alzheimer's disease (AD). Because the olfactory system is highly conserved across species, mouse models corresponding to various AD etiologies have been bred and used in numerous studies on olfactory disorders. The olfactory behavior test is a method required for early olfactory dysfunction detection in AD model mice. Here, we review the olfactory evaluation of AD model mice, focusing on traditional olfactory detection methods, olfactory behavior involving the olfactory cortex, and the results of olfactory behavior in AD model mice, aiming to provide some inspiration for further development of olfactory detection methods in AD model mice.

Apoptosis, rather than neurogenesis, induces significant hippocampal-dependent learning and memory impairment in chronic low Cd2+ exposure.

Cadmium (Cd), a ubiquitous toxic heavy metal, with the intractable trait of low degradation, can induce multiple organ damage. Whereas, far less is known about its neurotoxicity and the specific mechanism in the chronic low Cd exposure. To investigate the chronic neurotoxicity of Cd2+ , we traced its effects for up to 30 months in mice which were exposed to Cd2+ by drinking the mimicking Cd-polluted water. We found the toxicity of chronic Cd exposure was a process associated with the transition from autophagy to apoptosis, and the switch of autophagy-apoptosis was Cd dose-dependent with the threshold of [Cd2+ ] 0.04 mg/L. Furthermore, JNK was found to be a hub molecule orchestrated the switch of autophagy-apoptosis by interacting with Sirt1 and p53. At last, the hippocampus-dependent learning and memory was damaged by continuous neuron apoptosis rather than deficit of neurogenesis. Therefore, elucidation of the effect, process, and potential molecular mechanism of the chronic low Cd2+ exposure is important for controlling of the environmental-pollutant Cd.

FLT4/VEGFR3 activates AMPK to coordinate glycometabolic reprogramming with autophagy and inflammasome activation for bacterial elimination.

Macrophages rapidly undergo glycolytic reprogramming in response to macroautophagy/autophagy, inflammasome activation and pyroptosis for the clearance of bacteria. Identification the key molecules involved in these three events will provide critical potential therapeutic applications. Upon S. typhimurium infection, FLT4/VEGFR3 and its ligand VEGFC were inducibly expressed in macrophages, and FLT4 signaling inhibited CASP1 (caspase 1)-dependent inflammasome activation and pyroptosis but enhanced MAP1LC3/LC3 activation for elimination of the bacteria. Consistently, FLT4 mutants lacking the extracellular ligand-binding domain increased production of the proinflammatory metabolites such as succinate and lactate, and reduced antimicrobial metabolites including citrate and NAD(P)H in macrophages and liver upon infection. Mechanistically, FLT4 recruited AMP-activated protein kinase (AMPK) and phosphorylated Y247 and Y441/442 in the PRKAA/alpha subunit for AMPK activation. The AMPK agonist AICAR could rescue glycolytic reprogramming and inflammasome activation in macrophages expressing the mutant FLT4, which has potential translational application in patients carrying Flt4 mutations to prevent recurrent infections. Collectively, we have elucidated that the FLT4-AMPK module in macrophages coordinates glycolytic reprogramming, autophagy, inflammasome activation and pyroptosis to eliminate invading bacteria.Abbreviations: 3-MA: 3-methyladenine; AICAR: 5-aminoimidazole-4-carboxamide1-ß-D-ribofuranoside; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; BMDM: bone marrow-derived macrophage; CASP1: caspase 1; CFUs: colony-forming units; FLT4/VEGFR3: FMS-like tyrosine kinase 4; GFP: green fluorescent protein; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PEM: peritoneal exudate macrophage; PRKAA1/AMPKα1: protein kinase, AMP-activated, alpha 1 catalytic subunit; PYCARD/ASC: PYD and CARD domain containing; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TLR4: toll-like receptor 4; ULK1: unc-51 like autophagy activating kinase 1; VEGFC: vascular endothelial growth factor C; WT: wild type.

Effect of Sensory Deprivation of Nasal Respiratory on Behavior of C57BL/6J Mice.

Nasal breathing is a dynamic cortical organizer involved in various behaviors and states, such as locomotion, exploration, memory, emotion, introspection. However, the effect of sensory deprivation of nasal respiratory breath (NRD) on behavior remain poorly understood. Herein, general locomotor activity, emotion, learning and memory, social interaction, and mechanical pain were evaluated using a zinc sulfate nasal irrigation induced nasal respiratory sensory deprivation animal model (ZnSO4-induced mouse model). In the open field test, the elevated O-maze test, and forced swim test, NRD mice exhibited depressive and anxiety-like behaviors. In memory-associated tests, NRD mice showed cognitive impairments in the hippocampal-dependent memory (Y maze, object recognition task, and contextual fear conditioning (CFC)) and amygdala-dependent memory (the tone-cued fear conditioning test (TFC)). Surprisingly, NRD mice did not display deficits in the acquisition of conditional fear in both CFC and TFC tests. Still, they showed significant memory retrieval impairment in TFC and enhanced memory retrieval in CFC. At the same time, in the social novelty test using a three-chamber setting, NRD mice showed impaired social and social novelty behavior. Lastly, in the von Frey filaments test, we found that the pain sensitivity of NRD mice was reduced. In conclusion, this NRD mouse model showed a variety of behavioral phenotypic changes, which could offer an important insight into the behavioral impacts of patients with anosmia or those with an impaired olfactory bulb (OB) (e.g., in COVID-19, Alzheimer's disease, Parkinson's disease, etc.).

Targeting lysophospholipid acid receptor 1 and ROCK kinases promotes antiviral innate immunity.

Growing evidence indicates the vital role of lipid metabolites in innate immunity. The lipid lysophosphatidic acid (LPA) concentrations are enhanced in patients upon HCV or SARS-CoV-2 infection, but the function of LPA and its receptors in innate immunity is largely unknown. Here, we found that viral infection promoted the G protein­coupled receptor LPA1 expression, and LPA restrained type I/III interferon production through LPA1. Mechanistically, LPA1 signaling activated ROCK1/2, which phosphorylated IRF3 Ser97 to suppress IRF3 activation. Targeting LPA1 or ROCK in macrophages, fibroblasts, epithelial cells, and LPA1 conditional KO mice promoted interferon-induced clearance of multiple viruses. LPA1 was colocalized with the receptor ACE2 in lung and intestine. Together with previous findings that LPA1 and ROCK1/2 promoted vascular leaking or lung fibrosis, we propose that the current available preclinical drugs targeting the LPA1-ROCK module might protect from SARS-CoV-2 or various virus infections in the intestine or lung.

HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis.

Although inflammation is critical for the clearance of pathogens, uncontrolled inflammation also contributes to the development of multiple diseases such as cancer and sepsis. Since NF-κB-mediated transactivation in the nucleus is pivotal downstream of various stimuli to induce inflammation, searching the nuclear-localized targets specifically regulating NF-κB activation will provide important therapeutic application. Here, we have identified that homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, increases its expression in inflammatory macrophages. Importantly, HIPK2 deficiency or overexpression could enhance or inhibit inflammatory responses in LPS-stimulated macrophages, respectively. HIPK2-deficient mice were more susceptible to LPS-induced endotoxemia and CLP-induced sepsis. Adoptive transfer of Hipk2+/- bone marrow cells (BMs) also aggravated AOM/DSS-induced colorectal cancer. Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation. Notably, the HDAC3 inhibitors protected wild-type or Hipk2-/- BMs-reconstituted mice from LPS-induced endotoxemia. Our findings suggest that the HIPK2-HDAC3-p65 module in macrophages restrains excessive inflammation, which may represent a new layer of therapeutic mechanism for colitis-associated colorectal cancer and sepsis.

M-CSF, IL-6, and TGF-ß promote generation of a new subset of tissue repair macrophage for traumatic brain injury recovery.

Traumatic brain injury (TBI) leads to high mortality rate. We aimed to identify the key cytokines favoring TBI repair and found that patients with TBI with a better outcome robustly increased concentrations of macrophage colony-stimulating factor, interleukin-6, and transforming growth factor-ß (termed M6T) in cerebrospinal fluid or plasma. Using TBI mice, we identified that M2-like macrophage, microglia, and endothelial cell were major sources to produce M6T. Together with the in vivo tracking of mCherry+ macrophages in zebrafish models, we confirmed that M6T treatment accelerated blood-borne macrophage infiltration and polarization toward a subset of tissue repair macrophages that expressed similar genes as microglia for neuroprotection, angiogenesis and cell migration. M6T therapy in TBI mice and zebrafish improved neurological function while blocking M6T-exacerbated brain injury. Considering low concentrations of M6T in some patients with poor prognostic, M6T treatment might repair TBI via generating a previously unidentified subset of tissue repair macrophages.

Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection.

Recent work suggests that cholesterol metabolism impacts innate immune responses against infection. However, the key enzymes or the natural products and mechanisms involved are not well elucidated. Here, we have shown that upon DNA and RNA viral infection, macrophages reduced 7-dehydrocholesterol reductase (DHCR7) expression. DHCR7 deficiency or treatment with the natural product 7-dehydrocholesterol (7-DHC) could specifically promote phosphorylation of IRF3 (not TBK1) and enhance type I interferon (IFN-I) production in macrophages. We further elucidated that viral infection or 7-DHC treatment enhanced AKT3 expression and activation. AKT3 directly bound and phosphorylated IRF3 at Ser385, together with TBK1-induced phosphorylation of IRF3 Ser386, to achieve IRF3 dimerization. Deletion of DHCR7 and the DHCR7 inhibitors including AY9944 and the chemotherapy drug tamoxifen promoted clearance of Zika virus and multiple viruses in vitro or in vivo. Taken together, we propose that the DHCR7 inhibitors and 7-DHC are potential therapeutics against emerging or highly pathogenic viruses.

YAP Aggravates Inflammatory Bowel Disease by Regulating M1/M2 Macrophage Polarization and Gut Microbial Homeostasis.

Inflammation, epithelial cell regeneration, macrophage polarization, and gut microbial homeostasis are critical for the pathological processes associated with inflammatory bowel disease (IBD). YAP (Yes-associated protein) is a key component of the Hippo pathway and was recently suggested to promote epithelial cell regeneration for IBD recovery. However, it is unclear how YAP regulates macrophage polarization, inflammation, and gut microbial homeostasis. Although YAP has been shown to promote epithelial regeneration and alleviate IBD, here we show that YAP in macrophages aggravates IBD, accompanied by the production of antimicrobial peptides and changes in gut microbiota. YAP impairs interleukin-4 (IL-4)/IL-13-induced M2 macrophage polarization while promoting lipopolysaccharide (LPS)/interferon γ (IFN-γ)-triggered M1 macrophage activation for IL-6 production. In addition, YAP expression is differently regulated during the induction of M2 versus M1 macrophages. This study suggests that fully understanding the multiple functions of YAP in different cell types is crucial for IBD therapy.

Olfactory deficit is associated with mitral cell dysfunction in the olfactory bulb of P301S tau transgenic mice.

Neurofibrillary tangles consisting of hyperphosphorylated tau (P-tau) are the neuropathological hallmark of Alzheimer's disease (AD), and olfaction disorder is an early symptom of AD. However, the link between P-tau aggregation and olfaction disorder remains unclear. In this study, the expression of P-tau in the olfactory bulb (OB), particularly in the mitral cell layer (MCL), external plexiform layer (EPL), and granule cell layer (GCL), of AD patients was found to be significantly higher than that in the OB of normal aging subjects, which suggested that these layers in the OB were susceptible to P-tau. The P301S tau transgenic mice (P301S mice) exhibit AD-like features, which can be characterized by olfactory dysfunction that precedes cognitive disorder. Importantly, the excessive P-tau expression in the OB of P301S mice, particularly in MCs, was associated with MC loss at 9 months of age, and decreased MC firing activities started to be observed at 2 months of age. Our results revealed that MCs might contribute to olfactory dysfunction in P301S mice. Furthermore, we described an aberrant dendro-dendritic synaptic structure between granule cells (GCs) and MCs and abnormal gamma oscillations in the EPL of the OB, and these findings indicated that P-tau might disrupt the regulation of MCs by GCs in P301S mice starting at 5 months of age. These data showed that the reduction in the MC firing frequency at 2 months of age might not be caused by GC suppression. Based on these findings, we speculated that MCs are a putative target for the treatment of P-tau-induced early olfactory dysfunction, and thus, an exploration of the specific causes and mechanisms of MC functional changes in P301S mice is crucial.

Impairment of Dendrodendritic Inhibition in the Olfactory Bulb of APP/PS1 Mice.

Olfactory dysfunction is an early event in Alzheimer's disease (AD). However, the mechanism underlying the AD-related changes in the olfactory bulb (OB) remains unknown. Granule cells (GCs) in the OB regulate the activity of mitral cells (MCs) through reciprocal dendrodendritic synapses, which is crucial for olfactory signal processing and odor discrimination. Nevertheless, the relationships between the morphological and functional changes of dendrodendritic synapses, particularly the local field potentials (LFPs) as a consequence of olfactory disorders in patients with AD have not been investigated. Here, we studied the morphological and functional changes induced by dendrodendritic inhibition in GCs onto MCs in the OB of amyloid precursor protein (APP)/PS1 mice and age-matched control mice during aging, particular, we focused on the effects of olfactory disorder in the dendrodendritic synaptic structures and the LFPs. We found that olfactory disorder was associated with increased amyloid-ß (Aß) deposits in the OB of APP/PS1 mice, and those mice also exhibited abnormal changes in the morphology of GCs and MCs, a decreased density of GC dendritic spines and impairments in the synaptic interface of dendrodendritic synapses between GCs and MCs. In addition, the aberrant enhancements in the γ oscillations and firing rates of MCs in the OB of APP/PS1 mice were recorded by multi-electrode arrays (MEAs). The local application of a GABAAR agonist nearly abolished the aberrant increase in γ oscillations in the external plexiform layer (EPL) at advanced stages of AD, whereas a GABAAR antagonist aggravated the γ oscillations. Based on our findings, we concluded that the altered morphologies of the synaptic structures of GCs, the dysfunction of reciprocal dendrodendritic synapses between MCs and GCs, and the abnormal γ oscillations in the EPL might contribute to olfactory dysfunction in AD.

Neuroprotective Effect of DAHP via Antiapoptosis in Cerebral Ischemia.

Aberrant production of nitric oxide following inducible nitric oxide synthase (iNOS) expression has been implicated in cell death and contributes to ischemic brain injury. Tetrahydrobiopterin (BH4) is an essential cofactor of NOS activity. Herein, we evaluated antiapoptotic and anti-inflammatory effects of diamino-6-hydroxypyrimidine (DAHP), a guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) inhibitor on focal cerebral ischemia-reperfusion injury by middle cerebral artery occlusion and reperfusion (MCAO) and investigated the underlying mechanism. Sprague-Dawley rats were divided into five groups. Experimental groups were subjected to 1.5 h transient MCAO. T2-weighted imaging was performed to evaluate brain edema lesions in the stroke rats. Infarct volume was estimated by 2,3,5-triphenyltetrazolium chloride (TTC) staining after 24 h reperfusion. Western blotting and immunohistochemistry were performed to detect iNOS, caspase-3, Bcl-2, COX-2, and TNF-α protein expressions. Apoptosis was determined by TUNEL staining. T2 hyperintensity changes were observed in primary ischemic region. DAHP pretreatment significantly suppressed iNOS overexpression, caspase-3, and TNF-α. There was also attenuation of neuronal apoptosis with decrement in proteins Bcl-2 and COX-2 expressions. On the basis of our results, we hypothesize DAHP to have a neuroprotective function against focal cerebral ischemia and might attenuate brain injury by decreasing reactive oxygen species (ROS) production, subsequently inhibiting apoptosis.

The roles and mechanisms of MST1/2 in the innate immune response.

The Hippo signaling pathway regulates cell proliferation, organ size and tissue regeneration through a series of kinase cascades. MST1/2 is the mammalian orthologue of the core kinase Hippo, which is crucial for the activation of downstream signaling. Additionally, MST1/2 has been reported to play important roles in cell differentiation, morphology and cytoskeleton reorganization. Recent evidence suggests that MST1/2 is involved in the regulation of T cell adhesion, migration, homing and Treg cell maturation and functions. Interestingly, these processes are not dependent on the canonical, but a non-canonical Hippo signaling pathway. More recent studies have revealed that MST1/2 mediates the innate immune response against pathogens or viruses, especially on macrophage phagocytosis as well as cytokines and ROS production. MST1/2 is associated with various diseases, such as bacterial or viral infection, inflammation-related cancer, and atherosclerosis. In this review, we summarize recent findings on the functions of MST1/2 in the innate immune response and inflammation-related diseases.

Runt-related Transcription Factor 1 (RUNX1) Binds to p50 in Macrophages and Enhances TLR4-triggered Inflammation and Septic Shock.

An appropriate inflammatory response plays critical roles in eliminating pathogens, whereas an excessive inflammatory response can cause tissue damage. Runt-related transcription factor 1 (RUNX1), a master regulator of hematopoiesis, plays critical roles in T cells; however, its roles in Toll-like receptor 4 (TLR4)-mediated inflammation in macrophages are unclear. Here, we demonstrated that upon TLR4 ligand stimulation by lipopolysaccharide (LPS), macrophages reduced the expression levels of RUNX1 Silencing of Runx1 attenuated the LPS-induced IL-1ß and IL-6 production levels, but the TNF-α levels were not affected. Overexpression of RUNX1 promoted IL-1ß and IL-6 production in response to LPS stimulation. Moreover, RUNX1 interacted with the NF-κB subunit p50, and coexpression of RUNX1 with p50 further enhanced the NF-κB luciferase activity. Importantly, treatment with the RUNX1 inhibitor, Ro 5-3335, protected mice from LPS-induced endotoxic shock and substantially reduced the IL-6 levels. These findings suggest that RUNX1 may be a new potential target for resolving TLR4-associated uncontrolled inflammation and preventing sepsis.

TET3 Inhibits Type I IFN Production Independent of DNA Demethylation.

Type I interferons (IFNs) play both beneficial and harmful roles in antiviral responses. Precise regulation of host type I IFNs is thus needed to prevent immune dysregulation. Here, we find that the DNA demethylase TET3 is a negative regulator of IFN-ß in response to poly(I:C) stimulation or viral infection. Deletion of TET3 enhances antiviral responses, with elevated expression of IFN-ß and IFN-stimulated genes. The catalytic domain of TET3 was critical for the suppression of IFN-ß production, but TET3 enzymatic activity was dispensable. Instead, the catalytic domain of TET3 interacts with HDAC1 and SIN3A, thus enhancing their binding to the Ifnb1 promoter. Our study demonstrates that TET3 negatively regulates type I IFN production independent of DNA demethylation. This not only sheds light on TET3 as a signaling protein in immune cells for gene regulation but also will help to develop strategies to prevent type I IFN-related disease.