Single Stage Nasal Reconstruction for Solitary Neurofibroma Isolated in the Columella.

Neurofibromas are benign peripheral nerve sheath tumors that can originate from several elements of peripheral nerves, including axons, Schwann cells, endoneurial fibroblasts, and perineurial cells. The occurrence of a solitary neurofibroma in the external nose, especially that isolated in the nasal columella, is extremely rare. To the best of our knowledge, only 4 cases of solitary neurofibromas in the external nose have been reported in the English literature: on the nasal dorsum, tip, and pyriform aperture, all originating from the trigeminal nerve. We report the first case of a solitary neurofibroma isolated in the nasal columella, which we found in an otherwise healthy 42-year-old man. We completely resected this tumor with a negative resection margin and performed reconstruction with a bilateral spreader graft and caudal septal extension graft using autologous septal cartilage. The postoperative course was successful in both cosmetic and functional results, with no sensory changes at the 1-year follow-up. Surgical treatment for this lesion was challenging due to the cosmetically obvious location and high rate of recurrence. A review of the literature highlights the clinical and histological characteristics, differential diagnosis, and management of solitary neurofibroma of the external nose.

Correction: Kim et al. Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice. Antioxidants 2021, 10, 1954.

In the original publication [...].

18:0 Lyso PC Derived by Bioactivity-Based Molecular Networking from Lentil Mutant Lines and Its Effects on High-Fat Diet-Induced Obese Mice.

Lentil (Lens culinaris; Fabaceae), one of the major pulse crops in the world, is an important source of proteins, prebiotics, lipids, and essential minerals as well as functional components such as flavonoids, polyphenols, and phenolic acids. To improve crop nutritional and medicinal traits, hybridization and mutation are widely used in plant breeding research. In this study, mutant lentil populations were generated by γ-irradiation for the development of new cultivars by inducing genetic diversity. Molecular networking via Global Natural Product Social Molecular Networking web platform and dipeptidyl peptide-IV inhibitor screening assay were utilized as tools for structure-based discovery of active components in active mutant lines selected among the lentil population. The bioactivity-based molecular networking analysis resulted in the annotation of the molecular class of phosphatidylcholine (PC) from the most active mutant line. Among PCs, 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (18:0 Lyso PC) was selected for further in vivo study of anti-obesity effect in a high-fat diet (HFD)-induced obese mouse model. The administration of 18:0 Lyso PC not only prevented body weight gain and decreased relative gonadal adipose tissue weight, but also attenuated the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and leptin in the sera of HFD-induced obese mice. Additionally, 18:0 Lyso PC treatment inhibited the increase of adipocyte area and crown-like structures in adipose tissue. Therefore, these results suggest that 18:0 Lyso PC is a potential compound to have protective effects against obesity, improving obese phenotype induced by HFD.

Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice.

The run/cysteine-rich-domain-containing Beclin1-interacting autophagy protein (Rubicon) is essential for the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by interacting with p22phox to trigger the production of reactive oxygen species (ROS) in immune cells. In a previous study, we demonstrated that the interaction of Rubicon with p22phox increases cellular ROS levels. The correlation between Rubicon and mitochondrial ROS (mtROS) is poorly understood. Here, we report that Rubicon interacts with p22phox in the outer mitochondrial membrane in macrophages and patients with human ulcerative colitis. Upon lipopolysaccharide (LPS) activation, the binding of Rubicon to p22phox was elevated, and increased not only cellular ROS levels but also mtROS, with an impairment of mitochondrial complex III and mitochondrial biogenesis in macrophages. Furthermore, increased Rubicon decreases mitochondrial metabolic flux in macrophages. Mito-TIPTP, which is a p22phox inhibitor containing a mitochondrial translocation signal, enhances mitochondrial function by inhibiting the association between Rubicon and p22phox in LPS-primed bone-marrow-derived macrophages (BMDMs) treated with adenosine triphosphate (ATP) or dextran sulfate sodium (DSS). Remarkably, Mito-TIPTP exhibited a therapeutic effect by decreasing mtROS in DSS-induced acute or chronic colitis mouse models. Thus, our findings suggest that Mito-TIPTP is a potential therapeutic agent for colitis by inhibiting the interaction between Rubicon and p22phox to recover mitochondrial function.

Chemical and Biological Profiles of Dendrobium in Two Different Species, Their Hybrid, and Gamma-Irradiated Mutant Lines of the Hybrid Based on LC-QToF MS and Cytotoxicity Analysis.

The Dendrobium species (Orchidaceae) has been cultivated as an ornamental plant as well as used in traditional medicines. In this study, the chemical profiles of Dendrobii Herba, used as herbal medicine, Dendrobium in two different species, their hybrid, and the gamma-irradiated mutant lines of the hybrid, were systematically investigated via ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QToF MS). Among the numerous peaks detected, 17 peaks were unambiguously identified. Gigantol (1), (1R,2R)-1,7-hydroxy-2,8-methoxy-2,3-dihydrophenanthrene-4(1H)-one (2), tristin (3), (-)-syringaresinol (4), lusianthridin (5), 2,7-dihydroxy-phenanthrene-1,4-dione (6), densiflorol B (7), denthyrsinin (8), moscatilin (9), lusianthridin dimer (10), batatasin III (11), ephemeranthol A (12), thunalbene (13), dehydroorchinol (14), dendrobine (15), shihunine (16), and 1,5,7-trimethoxy-2-phenanthrenol (17), were detected in Dendrobii Herba, while 1, 2, and 16 were detected in D. candidum, 1, 11, and 16 in D. nobile, and 1, 2, and 16 in the hybrid, D. nobile × candidum. The methanol extract taken of them was also examined for cytotoxicity against FaDu human hypopharynx squamous carcinoma cells, where Dendrobii Herba showed the greatest cytotoxicity. In the untargeted metabolite analysis of 436 mutant lines of the hybrid, using UPLC-QToF MS and cytotoxicity measurements combined with multivariate analysis, two tentative flavonoids (M1 and M2) were evaluated as key markers among the analyzed metabolites, contributing to the distinction between active and inactive mutant lines.

Dendrobine Inhibits γ-Irradiation-Induced Cancer Cell Migration, Invasion and Metastasis in Non-Small Cell Lung Cancer Cells.

The use of ionizing radiation (IR) during radiotherapy can induce malignant effects, such as metastasis, which contribute to poor prognoses in lung cancer patients. Here, we explored the ability of dendrobine, a plant-derived alkaloid from Dendrobium nobile, to improve the efficacy of radiotherapy in non-small cell lung cancer (NSCLC). We employed Western blotting, quantitative real-time (qRT)-PCR, transwell migration assays, and wound-healing assays to determine the effects of dendrobine on the migration and invasion of A549 lung cancer cells in vitro. Dendrobine (5 mm) inhibited γ-irradiation-induced migration and invasion of A549 cells by suppressing sulfatase2 (SULF2) expression, thus inhibiting IR-induced signaling. To investigate the inhibitory effects of dendrobine in vivo, we established a mouse model of IR-induced metastasis by injecting BALB/c nude mice with γ-irradiated A549 cells via the tail vein. As expected, injection with γ-irradiated cells increased the number of pulmonary metastatic nodules in mice (0 Gy/DPBS, 9.8 ± 1.77; 2 Gy/DPBS, 20.87 ± 1.42), which was significantly reduced with dendrobine treatment (2 Gy/Dendrobine, 10.87 ± 0.71), by prevention of IR-induced signaling. Together, these findings demonstrate that dendrobine exerts inhibitory effects against γ-irradiation-induced invasion and metastasis in NSCLC cells in vitro and in vivo at non cytotoxic concentrations. Thus, dendrobine could serve as a therapeutic enhancer to overcome the malignant effects of radiation therapy in patients with NSCLC.

Isoegomaketone from Perilla frutescens (L.) Britt Stimulates MAPK/ERK Pathway in Human Keratinocyte to Promote Skin Wound Healing.

Skin wound healing is essential for recovery from injury, and delayed or impaired wound healing is a severe therapeutic challenge. Keratinocytes, a major component of the epidermis, play crucial roles in reepithelialization during wound healing including cell proliferation. Recent studies have shown that compounds from natural products have candidates for healing skin injury. Isoegomaketone (IK), isolated from leaves of Perilla frutescens var. crispa (Lamiaceae), has various bioactivities. However, the effect of IK on cutaneous wound healing processes has not been studied yet. In this study, we demonstrated that IK exhibits therapeutic wound healing effects using the human keratinocyte cell line HaCaT. Notably, IK promoted cell proliferation and migration in a dose-dependent manner in vitro, and treatment with 10 µM IK upregulated these processes by approximately 1.5-fold after 24 h compared with the control. IK induced the activation of the MAPK/ERK pathway and cell cycle progression to the S and G2/M phases. Thus, this study demonstrates IK as a potential candidate to upregulate wound healing that may provide therapeutic benefits to patients with delayed wound healing.

Host-Directed Therapy in Tuberculosis: Targeting Host Metabolism.

Mycobacterium tuberculosis (Mtb) has complex and intricate interactions with host immune cells. Mtb can survive, persist, and grow within macrophages and thereby circumvent detection by the innate immune system. Recently, the field of immunometabolism, which focuses on the link between metabolism and immune function, has provided us with an improved understanding of the role of metabolism in modulating immune function. For example, host immune cells can switch from oxidative phosphorylation to glycolysis in response to infection, a phenomenon known as the Warburg effect. In this state, immune cells are capable of amplifying production of both antimicrobial pro-inflammatory mediators that are critical for the elimination of bacteria. Also, cells undergoing the Warburg effect upregulate production of nitric oxide augment the synthesis of bioactive lipids. In this review, we describe our current understanding of the Warburg effect and discuss its role in promoting host immune responses to Mtb. In most settings, immune cells utilize the Warburg effect to promote inflammation and thereby eliminate invading bacteria; interestingly, Mtb exploits this effect to promote its own survival. A better understanding of the dynamics of metabolism within immune cells together with the specific features that contribute to the pathogenesis of tuberculosis (TB) may suggest potential host-directed therapeutic targets for promoting clearance of Mtb and limiting its survival in vivo.

Dietary schizophyllan reduces mitochondrial damage by activating SIRT3 in mice.

Schizophyllan (SPG), produced by Schizophyllum commune, is an exopolysaccharide with multiple academic and commercial uses, including in the food industry and for various medical functions. We previously demonstrated that SPG conjugated with c-Src peptide exerted a significant therapeutic effect on mouse models of the acute inflammatory diseases polymicrobial sepsis and ulcerative colitis. Here we extended these results by investigating whether SPG exerted a protective effect against mitochondrial damage in the liver via sirtuin 3 (SIRT3) induction, focusing on the deacetylation of succinate dehydrogenase A (SDHA) and superoxide dismutase 2 (SOD2). Liver damage models induced by alcohol or conjugated linoleic acid (CLA, which simulates lipodystrophy) in SIRT3-/-, SOD2-/-, and SDHA-/- mice were used. Results showed that dietary supplementation with SPG induced SIRT3 activation; this was involved in mitochondrial metabolic resuscitation that countered the adverse effects of alcoholic liver disease and CLA-induced damage. The mitochondrial SIRT3 mediated the deacetylation and activation of SOD2 in the liver and SDHA in adipose tissues, suggesting that SPG supplementation reduced ethanol-induced liver damage and CLA-induced adverse dietary effects via SIRT3-SOD2 and SIRT3-SDHA signaling, respectively. Together, these results suggest that dietary SPG has a previously unrecognized role in SIRT3-mediated mitochondrial metabolic resuscitation during mitochondria-related diseases.

Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive oxygen species (ROS) that are among the key markers for determining RA's pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA. Here, by combining mouse genetics and biochemistry with clinical tissue analysis, we reveal that in vivo Rubicon interacts with the p22phox subunit of NOX, which is necessary for increased ROS-mediated RA pathogenesis. Furthermore, we developed a series of new aryl propanamide derivatives consisting of tetrahydroindazole and thiadiazole as p22phox inhibitors and selected 2-(tetrahydroindazolyl)phenoxy-N-(thiadiazolyl)propanamide 2 (TIPTP, M.W. 437.44), which showed considerably improved potency, reaching an IC50 value up to 100-fold lower than an inhibitor that we previously synthesized reported N8 peptide-mimetic small molecule (blocking p22phox-Rubicon interaction). Notably, TIPTP treatment showed significant therapeutic effects a mouse model for RA. Furthermore, TIPTP had anti-inflammatory effects ex vivo in monocytes from healthy individuals and synovial fluid cells from RA patients. These findings may have clinical applications for the development of TIPTP as a small molecule inhibitor of the p22phox-Rubicon axis for the treatment of ROS-driven diseases such as RA.

Moscatilin Induces Apoptosis in Human Head and Neck Squamous Cell Carcinoma Cells via JNK Signaling Pathway.

Dendrobii Herba is an herbal medicine that uses the stems of Dendrobium species (Orchidacea). It has been traditionally used to treat fever, hydrodipsomania, stomach disorders, and amyotrophia. In our previous study, a bibenzyl compound, moscatilin, which is isolated from Dendrobii Herba, showed potent cytotoxicity against a FaDu human pharyngeal squamous carcinoma cell line. Prompted by this finding, we performed additional studies in FaDu cells to investigate the mechanism of action. Moscatilin induced FaDu cell death by using 5 µM of concentration and by mediating apoptosis, whereas cell proliferation following treatment with 1 µM of moscatilin was not suppressed to the same levels as by the anti-cancer agent, cisplatin. Apoptosis-related protein expression (cleaved caspase-8, cleaved caspase-7, cytochrome c, cleaved caspase-9, cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP) was increased by treating with 5 µM of moscatilin. This suggests that moscatilin-mediated apoptosis is associated with the extrinsic and intrinsic apoptotic signaling pathways. In addition, moscatilin-induced apoptosis was mediated by the c-Jun N-terminal kinase (JNK) signaling pathway. Overall, this study identified additional biological activity of moscatilin derived from natural products and suggested its potential application as a chemotherapeutic agent for the management of head and neck squamous cell carcinoma.

Latest Comprehensive Knowledge of the Crosstalk between TLR Signaling and Mycobacteria and the Antigens Driving the Process.

Tuberculosis, which is caused by Mycobacterium tuberculosis (Mtb), is among the most pressing worldwide problems. Mtb uniquely interacts with innate immune cells through various pattern recognition receptors. These interactions initiate several inflammatory pathways that play essential roles in controlling Mtb pathogenesis. Although the TLR signaling pathways have essential roles in numerous host's immune defense responses, the role of TLR signaling in the response to Mtb infection is still unclear. This review presents discussions on host-Mtb interactions in terms of Mtb-mediated TLR signaling. In addition, we highlight recent discoveries pertaining to these pathways that may help in new immunotherapeutic opportunities.

Protective roles of ginseng against bacterial infection.

Ginseng (Panax ginseng Meyer) is a well-known traditional herbal medicine that plays a protective role against microbial attack. Several studies have revealed its anti-cancer, anti-inflammatory, and immune-modulatory effects. Ginseng contains several components that vary according to the year of cultivation and the processing method used, such as heating, drying, and steaming, which induce different degrees of pharmacological activities. This review discusses the antibacterial effects of ginseng against pathogenic bacterial infections. We describe how ginseng regulates pathogenic factors that are harmful to the host and discuss the therapeutic potential of ginseng as a natural antibacterial drug to combat bacterial infectious disease, which is a global public health challenge. The components of ginseng could be novel alternatives to solve the growing problem of antibiotic resistance and toxicity.

Toxoplasma gondii GRA8 induces ATP5A1-SIRT3-mediated mitochondrial metabolic resuscitation: a potential therapy for sepsis.

The intracellular parasite Toxoplasma gondii has unique dense granule antigens (GRAs) that are crucial for host infection. Emerging evidence suggests that GRA8 of T. gondii is a promising serodiagnostic marker in toxoplasmosis. However, little is known about the intracellular regulatory mechanisms involved in GRA8-induced host responses. We found that GRA8 interacts with host proteins involved in mitochondria activation and might be useful as a therapeutic strategy for sepsis. Here, we show that protein kinase-Cα (PKCα)-mediated phosphorylation of T. gondii GRA8 (Thr220) is required for mitochondrial trafficking and regulates the interaction of C terminal of GRA8 with nucleotide binding domain of ATP5A1. Furthermore, GRA8 interacts with SIRT3 in mitochondria, facilitating ATP5A1 deacetylation (K506 and K531), adenosine triphosphate production and subsequent anti-septic activity in vivo. Taken together, these results demonstrate a new anti-sepsis therapeutic strategy using T. gondii GRA8-induced mitochondrial metabolic resuscitation. This strategy represents an urgently needed paradigm shift for therapeutic intervention.

CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22.

The tumor suppressor gene CD82/KAI1 is a member of the tetraspanin superfamily and organizes various membrane-based processes. Mycobacterium tuberculosis (MTB) persists in host macrophages by interfering with phagolysosome biogenesis and inflammatory responses, but the role of CD82 in controlling the intracellular survival of pathogenic mycobacteria within macrophages remains poorly understood. In this study, we demonstrated that the virulent MTB strain H37Rv (MTB Rv) induced CD82 promoter hypomethylation, resulting in CD82 expression. Targeting of the runt-related transcription factor 1 (RUNX1) by CD82 is essential for phagosome arrest via interacting with Rab5/22. This arrest is required for the intracellular growth of MTB in vitro and in vivo, but not for that of MTB H37Ra (MTB Ra) in macrophages. In addition, knockdown or knockout of CD82 or RUNX1 increased antibacterial host defense via phagolysosome biogenesis, inflammatory cytokine production, and subsequent antimicrobial activity both in vitro and in vivo. Notably, the levels of CD82 and RUNX1 in granulomas were elevated in tuberculosis (TB) patients, indicating that CD82 and RUNX1 have clinical significance in human TB. Our findings identify a previously unrecognized role of CD82 hypomethylation in the regulation of phagosome maturation, enhanced intracellular survival, and the innate host immune response to MTB. Thus, the CD82-RUNX1-Rab5/22 axis may be a previously unrecognized virulence mechanism of MTB pathogenesis.

ESRRA (estrogen-related receptor α) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense.

The orphan nuclear receptor ESRRA (estrogen-related receptor α) is a key regulator of energy homeostasis and mitochondrial function. Macroautophagy/autophagy, an intracellular degradation process, is a critical innate effector against intracellular microbes. Here, we demonstrate that ESRRA is required for the activation of autophagy to promote innate antimicrobial defense against mycobacterial infection. AMP-activated protein kinase pathway and SIRT1 (sirtuin 1) activation led to induction of ESRRA, which is essential for autophagosome formation, in bone marrow-derived macrophages. ESRRA enhanced the transcriptional activation of numerous autophagy-related (Atg) genes containing ERR response elements in their promoter regions. Furthermore, ESRRA, operating in a feed-forward loop with SIRT1, was required for autophagy activation through deacetylation of ATG5, BECN1, and ATG7. Importantly, ESRRA deficiency resulted in a decrease of phagosomal maturation and antimicrobial responses against mycobacterial infection. Thus, we identify ESRRA as a critical activator of autophagy via both transcriptional and post-translational control to promote antimicrobial host responses.

Host-Directed Therapeutics as a Novel Approach for Tuberculosis Treatment.

Despite significant efforts to improve the treatment of tuberculosis (TB), it remains a prevalent infectious disease worldwide owing to the limitations of current TB therapeutic regimens. Recent work on novel TB treatment strategies has suggested that directly targeting host factors may be beneficial for TB treatment. Such strategies, termed host-directed therapeutics (HDTs), focus on host-pathogen interactions. HDTs may be more effective than the currently approved TB drugs, which are limited by the long durations of treatment needed and the emergence of drug-resistant strains. Targets of HDTs include host factors such as cytokines, immune checkpoints, immune cell functions, and essential enzyme activities. This review article discusses examples of potentially promising HDTs and introduces novel approaches for their development.

Toxoplasma gondii GRA7-Targeted ASC and PLD1 Promote Antibacterial Host Defense via PKCα.

Tuberculosis is a global health problem and at least one-third of the world's population is infected with Mycobacterium tuberculosis (MTB). MTB is a successful pathogen that enhances its own intracellular survival by inhibiting inflammation and arresting phago-lysosomal fusion. We previously demonstrated that Toxoplasma gondii (T. gondii) dense granule antigen (GRA) 7 interacts with TNF receptor-associated factor 6 via Myeloid differentiation primary response gene 88, enabling innate immune responses in macrophages. To extend these studies, we found that GRA7 interacts with host proteins involved in antimicrobial host defense mechanisms as a therapeutic strategy for tuberculosis. Here, we show that protein kinase C (PKC)α-mediated phosphorylation of T. gondii GRA7-I (Ser52) regulates the interaction of GRA7 with PYD domain of apoptosis-associated speck-like protein containing a carboxy-terminal CARD, which is capable of oligomerization and inflammasome activation can lead to antimicrobial defense against MTB. Furthermore, GRA7-III interacted with the PX domain of phospholipase D1, facilitating its enzyme activity, phago-lysosomal maturation, and subsequent antimicrobial activity in a GRA7-III (Ser135) phosphorylation-dependent manner via PKCα. Taken together, these results underscore a previously unrecognized role of GRA7 in modulating antimicrobial host defense mechanism during mycobacterial infection.

RNAi-mediated silencing of TNF-α converting enzyme to down-regulate soluble TNF-α production for treatment of acute and chronic colitis.

Elevated level of tumor necrosis factor-α (TNF-α), one of the inflammatory cytokines, is considered to be a potential target for the inflammatory bowel disease (IBD) therapy. Recently, TNF-α converting enzyme (TACE), a sheddase playing an important role in cleaving and releasing bioactive soluble TNF-α, has been challenged with inhibitors to treat inflammatory diseases. Here, we report a novel anti-TNF-α strategy using a short hairpin RNA silencing TACE (shTACE) to prevent and treat colitis. The shTACE formed stable complexes with nona-arginine-based bio-cleavable disulfide bond-linked poly (arginine) (PAs-s) for enhanced gene delivery. Systemically administered shTACE/PAs-s peptoplexes efficiently decreased TNF-α levels, increased survival and alleviated pathophysiological parameters representing colitis severity. Our results demonstrate effectiveness and safety of shTACE/PAs-s peptoplexes with the capacity of overcoming acute and chronic ulcerative colitis through modulation of excessive inflammatory responses in the colon, providing a strong potential as a therapeutic agent for a broad variety of inflammatory diseases.

Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock.

Sepsis is a clinical syndrome that complicates severe infection and is characterized by the systemic inflammatory response syndrome (SIRS), is a life threatening disease characterized by inflammation of the entire body. Upon microbial infection, p22phox-gp91phox NADPH oxidase (NOX) complexes produce reactive oxygen species (ROS) that are critical for the elimination of invading microbes. However, excess production of ROS represents a key element in the cascade of deleterious processes in sepsis. We have previously reported direct crosstalk between autophagy and phagocytosis machineries by demonstrating that the Rubicon protein interacts with p22phox upon microbial infection, facilitating phagosomal trafficking of the p22phox-gp91phox NOX complex to induce a ROS burst, inflammatory cytokine production, and thereby, potent anti-microbial activities. Here, we showed N8 peptide, an N-terminal 8-amino acid peptide derived from p22phox, was sufficient for Rubicon interaction and thus, capable of robustly blocking the Rubicon-p22phox interaction and profoundly suppressing ROS and inflammatory cytokine production. Consequently, treatment with the Tat-N8 peptide or a N8 peptide-mimetic small-molecule dramatically reduced the mortality associated with Cecal-Ligation-and-Puncture-induced polymicrobial sepsis in mice. This study demonstrates a new anti-sepsis therapeutic strategy by blocking the crosstalk between autophagy and phagocytosis innate immunity machineries, representing a potential paradigm shift for urgently needed therapeutic intervention against this life-threatening SIRS.