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.

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.

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.

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.

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.

The Immune Adaptor ADAP Regulates Reciprocal TGF-ß1-Integrin Crosstalk to Protect from Influenza Virus Infection.

Highly pathogenic avian influenza virus (HPAI, such as H5N1) infection causes severe cytokine storm and fatal respiratory immunopathogenesis in human and animal. Although TGF-ß1 and the integrin CD103 in CD8+ T cells play protective roles in H5N1 virus infection, it is not fully understood which key signaling proteins control the TGF-ß1-integrin crosstalk in CD8+ T cells to protect from H5N1 virus infection. This study showed that ADAP (Adhesion and Degranulation-promoting Adapter Protein) formed a complex with TRAF6 and TAK1 in CD8+ T cells, and activated SMAD3 to increase autocrine TGF-ß1 production. Further, TGF-ß1 induced CD103 expression via an ADAP-, TRAF6- and SMAD3-dependent manner. In response to influenza virus infection (i.e. H5N1 or H1N1), lung infiltrating ADAP-/- CD8+ T cells significantly reduced the expression levels of TGF-ß1, CD103 and VLA-1. ADAP-/- mice as well as Rag1-/- mice receiving ADAP-/- T cells enhanced mortality with significant higher levels of inflammatory cytokines and chemokines in lungs. Together, we have demonstrated that ADAP regulates the positive feedback loop of TGF-ß1 production and TGF-ß1-induced CD103 expression in CD8+ T cells via the TßRI-TRAF6-TAK1-SMAD3 pathway and protects from influenza virus infection. It is critical to further explore whether the SNP polymorphisms located in human ADAP gene are associated with disease susceptibility in response to influenza virus infection.

Hepatocellular carcinoma repression by TNFα-mediated synergistic lethal effect of mitosis defect-induced senescence and cell death sensitization.

UNLABELLED: Hepatocellular carcinoma (HCC) is a cancer lacking effective therapies. Several measures have been proposed to treat HCCs, such as senescence induction, mitotic inhibition, and cell death promotion. However, data from other cancers suggest that single use of these approaches may not be effective. Here, by genetic targeting of Survivin, an inhibitor of apoptosis protein (IAP) that plays dual roles in mitosis and cell survival, we identified a tumor necrosis factor alpha (TNFα)-mediated synergistic lethal effect between senescence and apoptosis sensitization in malignant HCCs. Survivin deficiency results in mitosis defect-associated senescence in HCC cells, which triggers local inflammation and increased TNFα. Survivin inactivation also sensitizes HCC cells to TNFα-triggered cell death, which leads to marked HCC regression. Based on these findings, we designed a combination treatment using mitosis inhibitor and proapoptosis compounds. This treatment recapitulates the therapeutic effect of Survivin deletion and effectively eliminates HCCs, thus representing a potential strategy for HCC therapy. CONCLUSION: Survivin ablation dramatically suppresses human and mouse HCCs by triggering senescence-associated TNFα and sensitizing HCC cells to TNFα-induced cell death. Combined use of mitotic inhibitor and second mitochondrial-derived activator of caspases mimetic can induce senescence-associated TNFα and enhance TNFα-induced cell death and synergistically eliminate HCC. (Hepatology 2016;64:1105-1120).

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.

Metabolomic analysis of key regulatory metabolites in hepatitis C virus-infected tree shrews.

Metabolomics is a powerful new technology that allows the assessment of global low-molecular-weight metabolites in a biological system and which shows great potential in biomarker discovery. Analysis of the key metabolites in body fluids has become an important part of improving the diagnosis, prognosis, and therapy of diseases. Hepatitis C virus (HCV) is a major leading cause of liver disease worldwide and a serious burden on public health. However, the lack of a small-animal model has hampered the analysis of HCV pathogenesis. We hypothesize that an animal model (Tupaia belangeri chinensis) of HCV would produce a unique characterization of metabolic phenotypes. Ultra-performance liquid-chromatography/electrospray ionization-SYNAPT-high-definition mass spectrometry (UPLC/ESI-SYNAPT-HDMS) coupled with pattern recognition methods and system analysis was carried out to obtain comprehensive metabolomics profiling and pathways of large biological data sets. Taurine, hypotaurine, ether lipid, glycerophospholipid, arachidonic acid, tryptophan, and primary bile acid metabolism pathways were acutely perturbed, and 38 differential metabolites were identified. More important, five metabolite markers were selected via the "significance analysis for microarrays" method as the most discriminant and interesting biomarkers that were effective for the diagnosis of HCV. Network construction has led to the integration of metabolites associated with the multiple perturbation pathways. Integrated network analysis of the key metabolites yields highly related signaling pathways associated with the differentially expressed proteins, which suggests that the creation of new treatment paradigms targeting and activating these networks in their entirety, rather than single proteins, might be necessary for controlling and treating HCV efficiently.

Autophagy upregulation and apoptosis downregulation in DAHP and triptolide treated cerebral ischemia.

It has previously been demonstrated that ischemic stroke activates autophagy pathways; however, the mechanism remains unclear. The aim of this study is to further investigate the role that autophagy plays in cerebral ischemia. 2, 4-diamino-6-hydroxy-pyrimidine (DAHP), for its nitric oxide synthase (NOS) inhibiting neuroprotective effect, and triptolide (TP), for its anti-inflammatory property, were selected to administer pre middle cerebral artery occlusion (MCAO). The drugs were administered 12 hours prior to MCAO. Both magnetic resonance imaging (MRI) and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining showed that the drugs reduce the area of infarction. Immunoblotting analysis revealed increases in Beclin-1 and myeloid cell leukelia-1(Mcl-1) in treated rats. This could be a contributing factor to the reduction in autophagy induced damage. Immunochemistry and western blot showed that mTOR expression in treated rats was marginally different 24 h after injury, and this could also be significant in the mechanism. Furthermore, terminal deoxynucleotidyl transferase- (TdT-) mediated dUTP nick end labeling (TUNEL) staining proved that the drugs are effective in reducing apoptosis. The upregulation of Beclin-1 and Mcl-1 and downregulation of Bcl-2, caspase-3, and the Bcl-2/Beclin-1 ratio infer that the neuroprotective effect of DAHP and TP act via the mediation of autophagy and apoptosis pathways.

Systematic hypothesis for post-stroke depression caused inflammation and neurotransmission and resultant on possible treatments.

Post-stroke depression (PSD) is a prevalent complex psychiatric disorder that causes delay to functional recovery from rehabilitation and also increases cognitive impairment. The etiology of PSD remains controversial and appears to be physical and psycho-social in origin, alone or in combination. The causes of PSD as well as the mechanisms conferring beneficial antidepressant effects in the context of ischemic brain injury are still unknown. In addition, appropriate treatment strategies for therapy to prevent stroke-induced depression-like behavior remain to be developed. This paper, therefore, proposes two hypotheses for post-stroke depression: The inflammatory hypothesis, which is the increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas causing the pathogenesis of post-stroke depression and the glutamate hypothesis, where the excess glucocorticoids released from stress-induced over-activation of hypothalamus-pituitary-adrenal (HPA) lead to dysfunction of glutamatergic transmission. Neurotrophins, especially brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) both play various roles in the central nervous system (CNS), attenuate apoptosis in cultured neurons, stimulate neurogenesis and increase survival and protect neuronal tissues from cell death induced by ischemia or depression. We also touch upon recent treatment strategies including inhibition of pro-inflammatory cytokines, SSRI, neurotrophins and cell-based therapies. In the present review, we provide an overview of recent evidence concerning the mechanisms of post-stroke depression and propose four prospective treatment strategies so as to provide references for clinical evidence-based medications.

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.

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.

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.

Synthesis and evaluation of ursolic acid derivatives as potent cytotoxic agents.

Structural modification was performed at the C-3 and C-28 positions of ursolic acid (UA). Ten UA derivatives with distinct electrical property were synthesized. They could be divided into two groups according to their charge under physiological conditions: (1) Group I negatively charged and (2) Group II positively charged. The anti-proliferative capability of the derivatives was evaluated against HepG2, AGS, HT-29 and PC-3 cells by the MTT assay. Flow cytometry and Annexin V/PI dual staining assay were carried out to explore the antitumor mechanism. The results showed the cytotoxic capacity of the compounds was: Group I

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.

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.