• Psoriasis
• autophagy
• bioinformatics
• hub genes
• immune infiltration

• Humans
• Sequestosome-1 Protein
• Psoriasis/diagnosis
• Psoriasis/genetics
• Biomarkers
• Computational Biology
• Autophagy/genetics
• ErbB Receptors

• Apoptosis
• Autophagy
• ER stress
• Immunity
• Immuno-proteostasis response
• JNK
• Leukocytes
• Oxidative stress
• Protein carbonyls
• Uremia
• Uremic toxins

• Humans
• Leukocytes, Mononuclear/metabolism
• Proteostasis
• Receptor for Advanced Glycation End Products/metabolism
• Hydrogen Peroxide/pharmacology
• Proteins
• Apoptosis/physiology

• Autophagy
• Cancer
• Chemoprevention
• Disease
• Inflammation

• (82060028) National Science Funding of China

• antigen-presenting cell
• dendritic cell
• helper T cell
• inflammatory bowel disease
• macrophage
• mucosal immunology

• Humans
• Intestinal Mucosa
• Macrophages
• Intestines
• Antigen-Presenting Cells
• Inflammatory Bowel Diseases

• TRIM7
• Zika virus
• antagonism of immune responses
• pathogenesis
• tropism
• ubiquitin

• Infant, Newborn
• Animals
• Female
• Humans
• Pregnancy
• Zika Virus
• Zika Virus Infection/complications
• Zika Virus Infection/drug therapy
• Virus Replication
• Microcephaly

• R01 AI166668 NIAID NIH HHS
• R01 AI155466 NIAID NIH HHS
• R01 AI134907 NIAID NIH HHS
• K12 HD052023 NICHD NIH HHS
• P01 AI150585 NIAID NIH HHS

Dendritic cells (DCs) are principal defense components that play multifactorial roles in translating innate immune responses to adaptive immunity in Mycobacterium tuberculosis (Mtb) infections. The heterogeneous nature of DC subsets follows their altered functions by interacting with other immune cells, Mtb, and its products, enhancing host defense mechanisms or facilitating pathogen evasion. Thus, a better understanding of the immune responses initiated, promoted, and amplified or inhibited by DCs in Mtb infection is an essential step in developing anti-tuberculosis (TB) control measures, such as host-directed adjunctive therapy and anti-TB vaccines. This review summarizes the recent advances in salient DC subsets, including their phenotypic classification, cytokine profiles, functional alterations according to disease stages and environments, and consequent TB outcomes. A comprehensive overview of the role of DCs from various perspectives enables a deeper understanding of TB pathogenesis and could be useful in developing DC-based vaccines and immunotherapies.

• Dendritic Cells
• Humans
• Immunity, Innate
• Mycobacterium tuberculosis
• Tuberculosis Vaccines
• Tuberculosis, Lymph Node

• Korea Health Industry Development Institute
• National Research Foundation of Korea

In the last few years, advancement in the analysis of the MHC class II (MHC-II) ligandome in several mouse and human haplotypes has increased our understanding of the molecular components that regulate the range and selection of the MHC-II presented peptides, from MHC class II molecule polymorphisms to the recognition of different conformers, functional differences in endosomal processing along the endocytic tract, and the interplay between the MHC class II chaperones DM and DO. The sum of all these variables contributes, qualitatively and quantitatively, to the composition of the MHC II ligandome, altogether ensuring that the immunopeptidome landscape is highly sensitive to any changes in the composition of the intra- and extracellular proteome for a comprehensive survey of the microenvironment for MHC II presentation to CD4 T cells.

• Animals
• Antigen Presentation/physiology
• CD4-Positive T-Lymphocytes
• Genes, MHC Class II
• Histocompatibility Antigens Class II/physiology
• Humans
• Proteome

• R01 AI137198 NIAID NIH HHS
• R01 AI146180 NIAID NIH HHS

Autophagy is a known mechanism of cells under internal stress that regulates cellular function via internal protein recycling and the cleaning up of debris, leading to healthy live cells. However, the stimulation of autophagy by external factors such as chemical compounds or viral infection mostly tends to induce apoptosis/cell death. This study hypothesizes that manipulation of the autophagy mechanism to the pro-cell survival and/or decreased pro-viral niche can be a strategy for effective antiviral and anticancer treatment. Cells susceptible to viral infection, namely LLC-MK2, normal monkey epithelium, and K562, human immune-related lymphocyte, which is also a cancer cell line, were treated with fludarabine nucleoside analog (Fdb), interferon alpha (IFN-α), and a combination of Fdb and IFN-α, and then were evaluated for signs of adaptive autophagy and STAT1 antiviral signaling by Western blotting and immunolabeling assays. The results showed that the low concentration of Fdb was able to activate an autophagy response in both cell types, as demonstrated by the intense immunostaining of LC3B foci in the autophagosomes of living cells. Treatment with IFN-α (10 U/mL) showed no alteration in the initiator of mTOR autophagy but dramatically increased the intracellular STAT1 signaling molecules in both cell types. Although in the combined Fdb and IFN-α treatment, both LLC-MK2 and K562 cells showed only slight changes in the autophagy-responsive proteins p-mTOR and LC3B, an adaptive autophagy event was clearly shown in the autophagosome of the LLC-MK2 cell, suggesting the survival phase of the normal cell. The combined effect of Fdb and IFN-α treatment on the antiviral response was identified by the level of activation of the STAT1 antiviral marker. Significantly, the adaptive autophagy mediated by Fdb was able to suppress the IFN-α-mediated pSTAT1 signaling in both cell types to a level that is appropriate for cellular function. It is concluded that the administration of an appropriate dose of Fdb and IFN-α in combination is beneficial for the treatment of some types of cancer and viral infection.

• Antiviral Agents/pharmacology
• Autophagy
• Cell Survival
• Humans
• Interferon-alpha/pharmacology
• K562 Cells
• TOR Serine-Threonine Kinases
• Vidarabine/analogs & derivatives

To investigate the mechanism of action of herb-partitioned moxibustion on CD from the perspective of autophagy and immunity.

The expression of microtubule-associated protein LC3II and SQSTM1/p62 in the colon tissues was detected by immunohistochemistry. Western blot was used to detect the expression of autophagic and immune-related proteins in the colon, such as LC3II, SQSTM1/p62, Beclin1, ATG16L1, NOD2, IRGM, IL-1β, IL-17, and TNF-β. mRNA levels of immune factors, such as IL-1β, IL-17, and TNF-β, and autophagy signaling molecules, such as PI3KC, AKT1, LKB1, and mTOR, were detected by RT-qPCR.

Herb-partitioned moxibustion reduced the protein levels of ATG16L1, NOD2, IRGM, LC3II, and Beclin1 (P < 0.01) and both the protein and mRNA levels of IL-1β, IL-17, and TNF-β in CD rats (P < 0.01 or P < 0.05), and it also increased the expression of SQSTM1/p62 protein (P < 0.01). The modulatory effects of herb-partitioned moxibustion on ATG16L1, NOD2, IRGM, LC3II, TNF-β, and IL-17 protein and IL-1β protein and mRNA were better than those of mesalazine (P < 0.01 or P < 0.05). Herb-partitioned moxibustion also reduced colon PI3KC, AKT1, and LKB1 mRNA expressions in CD rats (P < 0.01 or P < 0.05) and increased mTOR protein expression (P < 0.05). And the modulatory effect of herb-partitioned moxibustion on AKT1 mRNA was better than that of mesalazine (P < 0.05).

Herb-partitioned moxibustion may inhibit excessively activated autophagy and modulate the expression of immune-related factors by regulating the LKB1-mTOR-PI3KC signal transduction networks, thereby alleviating intestinal inflammation in CD rats.

Equine sarcoids, caused by bovine papillomaviruses, are equine skin tumors of fibroblastic origin. It is well known that bovine papillomaviruses are able to interfere with the survival and proliferation of cells by regulating autophagy, a mechanism implicated in the breakdown and reuse of old and damaged cellular material. The present study focused on the evaluation in equine sarcoids and normal skins of the expression level of some of the main proteins involved in the autophagic pathway, such as Beclin 1, LC3 and P62, by immunohistochemical and biochemical techniques. Results obtained in equine sarcoids suggested an alteration of the autophagic process which could lead to a predominance of a particular population of fibroblast. Those fibroblasts could survive longer in a hypoxic microenvironment and produce more and/or altered collagen, giving an origin to the equine sarcoid.

Background: It is well known that δ-bovine papillomaviruses (BPV-1, BPV-2 and BPV-13) are one of the major causative agents of equine sarcoids, the most common equine skin tumors. Different viruses, including papillomaviruses, evolved ingenious strategies to modulate autophagy, a complex process involved in degradation and recycling of old and damaged material. Methods: The aim of this study was to evaluate, by immunohistochemistry (IHC) and Western blot (WB) analysis, the expression of the main related autophagy proteins (Beclin 1, protein light chain 3 (LC3) and P62), in 35 BPV1/2 positive equine sarcoids and 5 BPV negative normal skin samples. Results: Sarcoid samples showed from strong-to-moderate cytoplasmic immunostaining, respectively, for Beclin 1 and P62 in >60% of neoplastic fibroblasts, while LC3 immunostaining was weak to moderate in ≤60% of neoplastic fibroblasts. Western blot analysis confirmed the specificity of the antibodies and revealed no activation of autophagic flux despite Beclin 1 overexpression in sarcoid samples. Conclusion: Results could suggest the activation of the initial phase of autophagy in equine sarcoids, and its impairment during the following steps. The impairment of autophagy could lead to a selection of a quiescent population of fibroblasts, which survive longer in a hypoxic microenvironment and produced more and/or altered collagen.

Tumor cells communicate with the stromal cells within the tumor microenvironment (TME) to create a conducive environment for tumor growth. One major avenue for mediating crosstalk between various cell types in the TME involves exchanges of molecular payloads in the form of extracellular vesicles/exosomes. Autophagy is a fundamental mechanism to maintain intracellular homeostasis but recent reports suggest that secretory autophagy plays an important role in promoting secretion of exosomes that are packaged with non-coding RNAs (ncRNAs) and other biomolecules from the donor cell. Uptake of exosomal autophagy-modulating ncRNAs by recipient cells may further perpetuate tumor progression.

Autophagy is a fundamental cellular homeostasis mechanism known to play multifaceted roles in the natural history of cancers over time. It has recently been shown that autophagy also mediates the crosstalk between the tumor and its microenvironment by promoting the export of molecular payloads such as non-coding RNA (ncRNAs) via LC3-dependent Extracellular Vesicle loading and secretion (LDELS). In turn, the dynamic exchange of exosomal ncRNAs regulate autophagic responses in the recipient cells within the tumor microenvironment (TME), for both tumor and stromal cells. Autophagy-dependent phenotypic changes in the recipient cells further enhance tumor growth and metastasis, through diverse biological processes, including nutrient supplementation, immune evasion, angiogenesis, and therapeutic resistance. In this review, we discuss how the feedforward autophagy-ncRNA axis orchestrates vital communications between various cell types within the TME ecosystem to promote cancer progression.

• Apaf1
• Bcl-2
• C. elegans
• apoptosis
• autophagy
• caspase
• electron microscopy

To construct a prognostic model based on immune-autophagy-related long noncoding RNA (IArlncRNAs), mainly to predict the overall survival rate (OS) of bladder cancer patients and investigate its possible mechanisms.

Transcriptome and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We identified the IArlncRNA by co-expression analysis, differential expression analysis, and Venn analysis. Then, we identified the independent prognostic IArlncRNAs by univariate Cox regression, LASSO regression, and multivariate Cox regression analysis. Moreover, we constructed the prognostic model based on the independent prognostic IArlncRNAs and clinical features. The proportion of 22 immune cell subtypes was analyzed by the CIBERSORT algorithm. Besides, we identified the differential proportion of 22 immune cell subtypes between the high- and low-risk groups. In addition, we identified the correlation between immune-infiltrating cells (screened by univariate Cox regression and multivariate Cox regression analysis) and IArlncRNAs by Pearson correlation analysis. Finally, we estimated the half-maximal inhibitory concentration (IC₅₀) of chemotherapeutic drugs in patients with bladder cancer based on the pRRophetic algorithm.

Four IArlncRNAs were identified as independent prognostic factors, including AL136084.3, AC006270.1, Z84484.1, and AL513218.1. The OS of patients in the high-risk group was significantly worse compared to the low-risk group. The nomogram showed an excellent predictive effect with the C-index of 0.64. The calibration chart showed a good actual vs. predicted probability. B cells naïve, T cells CD8, T cells CD4 memory resting, T cells follicular helper, macrophages M1, dendritic resting and activated cells had higher infiltrations in the low-risk group and lower infiltration of macrophages M2. The fraction of macrophages M2 was positively associated with AL136084.3. The fraction of T cells CD8 was positively associated with Z84484.1. The fraction of M + macrophages M0 was negatively associated with Z84484.1. Further, we identified the differential IC₅₀ of 24 chemotherapeutic drugs between the high- and low-risk groups.

The prognostic model based on 4 IArlncRNAs showed an excellent predictive effect. Furthermore, we reasonably speculated that IArlncRNAs are directly or indirectly involved in the immune regulation of the tumor microenvironment (TME), as well as autophagy.

• Long noncoding RNA (lncRNAs)
• bladder cancer
• nomogram
• prognostic model
• risk score

• COVID-19
• ERAD
• SARS-CoV-2
• autophagy
• coronaviruses
• viral infection

• Antiviral Agents/pharmacology
• Autophagosomes/metabolism
• Autophagosomes/virology
• Autophagy/drug effects
• COVID-19/metabolism
• COVID-19/pathology
• COVID-19/virology
• Coronavirus/classification
• Coronavirus/pathogenicity
• Coronavirus Infections/drug therapy
• Coronavirus Infections/metabolism
• Coronavirus Infections/pathology
• Coronavirus Infections/virology
• Endoplasmic Reticulum-Associated Degradation/drug effects
• Humans
• SARS-CoV-2/pathogenicity
• Virus Replication/drug effects
• COVID-19 Drug Treatment

• IL-15
• Mycobacterium leprae
• autophagy
• leprosy or T1R
• lysosomes
• macrophage or THP-1
• phagosome

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Autophagy/genetics
• Cells, Cultured
• Child
• Cytokines/genetics
• Female
• Gene Expression/genetics
• Humans
• Interferon-gamma/genetics
• Interleukin-15/genetics
• Leprosy/genetics
• Leprosy/microbiology
• Male
• Middle Aged
• Mycobacterium leprae/pathogenicity
• Skin/metabolism
• Skin/microbiology
• THP-1 Cells/metabolism
• Young Adult

• Exocytosis
• Inflammation
• LC3-Associated phagocytosis (LAP)
• MHC restricted Antigen presentation
• Viral envelope

• Apoptosis
• Autoimmune diseases
• Autophagy
• miRNAs

• macroautophagy
• phagocytosis
• mhc class ii

• autophagy
• immune cell
• tumour cell
• tumour immunity

• IRGM
• Melanoma
• autophagy
• prognostic biomaker

Autophagy is a constitutive pathway that allows the lysosomal degradation of damaged components. This conserved process is essential for metabolic plasticity and tissue homeostasis and is crucial for mammalian post-mitotic cells. Autophagy also controls stem cell fate and defective autophagy is involved in many pathophysiological processes. In this review, we focus on established and recent breakthroughs aimed at elucidating the impact of autophagy in differentiation and homeostasis maintenance of endothelium, muscle, immune system, and brain providing a suitable framework of the emerging results and highlighting the pivotal role of autophagic response in tissue functions, stem cell dynamics and differentiation rates.

• autophagy
• tissue differentiation
• tissue homeostasis
• tissue pathophysiology
• tissue remodeling

The tumor microenvironment (TME) is complex, and its composition and dynamics determine tumor fate. From tumor cells themselves, with their capacity for unlimited replication, migration, and invasion, to fibroblasts, endothelial cells, and immune cells, which can have pro and/or anti-tumor potential, interaction among these elements determines tumor progression. The understanding of molecular pathways involved in immune escape has permitted the development of cancer immunotherapies. Targeting molecules or biological processes that inhibit antitumor immune responses has allowed a significant improvement in cancer patient’s prognosis. Autophagy is a cellular process required to eliminate dysfunctional proteins and organelles, maintaining cellular homeostasis. Usually a process associated with protection against cancer, autophagy associated to cancer cells has been reported in response to hypoxia, nutrient deficiency, and oxidative stress, conditions frequently observed in the TME. Recent studies have shown a paradoxical association between autophagy and tumor immune responses. Tumor cell autophagy increases the expression of inhibitory molecules, such as PD-1 and CTLA-4, which block antitumor cytotoxic responses. Moreover, it can also directly affect antitumor immune responses by, for example, degrading NK cell-derived granzyme B and protecting tumor cells. Interestingly, the activation of autophagy on dendritic cells has the opposite effects, enhancing antigen presentation, triggering CD8⁺ T cells cytotoxic activity, and reducing tumor growth. Therefore, this review will focus on the most recent aspects of autophagy and tumor immune environment. We describe the dual role of autophagy in modulating tumor immune responses and discuss some aspects that must be considered to improve cancer treatment.

• antitumor immunity
• macroautophagy
• onco immunology
• tumor immune evasion
• tumor microenvironment

• Adaptive immunity
• CD8(+) T cell exhaustion
• CD8(+) T cell metabolism
• Chronic HBV infection
• Hepatitis B virus
• Metabolic restoration

Metformin is an oral antihyperglycemic drug widely used to treat type 2 diabetes, acting via indirect activation of 5′ Adenosine Monophosphate-activated Protein Kinase (AMPK). Actually, evidence has accumulated of an intriguing anti-inflammatory activity, mainly mediated by AMPK through a variety of mechanisms such as the inhibition of cytokine-stimulated Nuclear Factor-κB (NF-κB) and the downregulation of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathways. Moreover, AMPK plays an important role in the modulation of T lymphocytes and other pivotal cells of the innate immune system. The current understanding of these AMPK effects provides a strong rationale for metformin repurposing in the management of autoimmune and inflammatory conditions. Several studies demonstrated metformin’s beneficial effects on both animal and human rheumatologic diseases, especially on rheumatoid arthritis. Unfortunately, even though data are large and remarkable, they almost exclusively come from experimental investigations with only a few from clinical trials. The lack of support from prospective placebo-controlled trials does not allow metformin to enter the therapeutic repertoire of rheumatologists. However, a large proportion of rheumatologic patients can currently benefit from metformin, such as those with concomitant obesity and type 2 diabetes, two conditions strongly associated with rheumatoid arthritis, osteoarthritis, and gout, as well as those with diabetes secondary to steroid therapy.

• autoimmune diseases
• inflammation
• metformin
• rheumatology
• type 2 diabetes

• Host-pathogen interaction
• Macrophage
• Signal pathway
• Xenophagy

• Animals
• Bacteria/immunology
• Host-Pathogen Interactions/immunology
• Humans
• Immunity, Innate/immunology
• Lysosomes/immunology
• Macroautophagy/immunology
• Macrophages/immunology

Recent studies have indicated that the Zika virus (ZIKV) has a significant impact on the fetal brain, and autophagy is contributing to host immune response and defense against virus infection. Here, we demonstrate that ZIKV infection triggered increased LC3 punctuation in mouse monocyte-macrophage cell line (RAW264.7), mouse microglial cell line (BV2), and hindbrain tissues, proving the occurrence of autophagy both in vitro and in vivo. Interestingly, manual intervention of autophagy, like deficiency inhibited by 3-MA, can reduce viral clearance in RAW264.7 cells upon ZIKV infection. Besides, specific siRNA strategy confirmed that autophagy can be activated through Atg7-Atg5 and type I IFN signaling pathway upon ZIKV infection, while knocking down of Atg7 and Atg5 effectively decreased the ZIKV clearance in phagocytes. Furthermore, we analyzed that type I IFN signaling could contribute to autophagic clearance of invaded ZIKV in phagocytes. Taken together, our findings demonstrate that ZIKV-induced autophagy is favorable to activate host immunity, particularly through type I IFN signaling, which participates in host protection and defense against ZIKV infection.

• Autophagy
• BIF
• Intestinal immune system
• Intestinal microbiota
• Kawasaki disease

• Bifidobacterium
• Caco-2 Cells
• Humans
• Inflammation/metabolism
• Inflammation/pathology
• Inflammation/prevention & control
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology
• MAP Kinase Signaling System
• Mucocutaneous Lymph Node Syndrome/metabolism
• Mucocutaneous Lymph Node Syndrome/pathology
• Mucocutaneous Lymph Node Syndrome/prevention & control
• NF-kappa B/metabolism
• Tumor Necrosis Factor-alpha/metabolism
• Tumor Necrosis Factor-alpha/pharmacokinetics
• p38 Mitogen-Activated Protein Kinases/metabolism

• ATG5
• PRDM1
• hepatitis B virus infection
• intergenic region
• single-nucleotide polymorphism

• Akt
• autophagy
• mTOR
• neonatal HIE
• perinatal nicotine

In liver transplantation (LT), although various immunosuppressants have been used in clinical practice, acute rejection remains a common complication that significantly shortens recipient survival. In recent years, manipulating immune tolerance has been regarded as one of the promising solutions to rejection. Autophagy, an evolutionarily conserved protein degradation system, has been reported to be involved in immune rejection and may be a target to establish immune tolerance. However, the role of autophagy in acute rejection reaction after LT has not been elucidated. Here, we showed that the autophagy of CD8⁺ T cells was strongly enhanced in patients with graft rejection and that the autophagy level was positively correlated with the severity of rejection. Similar findings were observed in a rat acute hepatic rejection model. Furthermore, administration of the autophagy inhibitor 3-methyladenine (3-MA) largely decreased the viability and function of CD8⁺ T cells through inhibiting autophagy, which significantly prolonged graft survival in rats. In addition, inhibiting the autophagy of activated CD8⁺ T cells in vitro considerably suppressed mitochondria mediated survival and downregulated T cell function.

Conclusions: We first showed that the inhibition of autophagy significantly prolongs liver allograft survival by promoting the apoptosis of CD8⁺ T cells, which may provide a novel strategy for immune tolerance induction.

• T cell
• acute rejection
• apoptosis
• autophagy
• liver transplantation

• CD4+ T cells
• MHC class II loading compartment
• Macroautophagy

• cell death
• entomopathogenic fungi
• fungal infection
• immunity
• tick

Aging Western societies are facing an increasing prevalence of chronic autoimmune-mediated inflammatory disorders (AIMIDs) for which treatments that are safe and effective are scarce. One of the main reasons for this situation is the lack of animal models, which accurately replicate clinical and pathological aspects of the human diseases. One important AIMID is the neuroinflammatory disease multiple sclerosis (MS), for which the mouse experimental autoimmune encephalomyelitis (EAE) model has been frequently used in preclinical research. Despite some successes, there is a long list of experimental treatments that have failed to reproduce promising effects observed in murine EAE models when they were tested in the clinic. This frustrating situation indicates a wide validity gap between mouse EAE and MS. This monography describes the development of an EAE model in nonhuman primates, which may help to bridge the gap.

• CD4(+) T cell stimulation
• CD8(+) T cell responses
• LC3 associated phagocytosis (LAP)
• MHC class I internalization
• MHC class II antigen processing

• CLE-10
• LC3
• MDA-MB-231
• PI3K/AKT/mTOR
• apoptosis
• autophagy

• Apoptosis/drug effects
• Asteraceae/chemistry
• Autophagy/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Female
• Flow Cytometry
• Humans
• Lactones/pharmacology
• Microscopy, Electron, Transmission
• Microtubule-Associated Proteins/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Sesquiterpenes/pharmacology
• Signal Transduction/drug effects
• TOR Serine-Threonine Kinases/metabolism

• Chronic inflammation
• diabetes
• immune aging
• wound healing

• Cytokines/immunology
• Diabetes Mellitus/immunology
• Diabetic Foot/immunology
• Humans
• Hyperglycemia/immunology
• Immunosenescence/immunology
• Inflammation/immunology
• T-Lymphocytes/immunology
• Wound Healing/immunology

• P20 GM109096 NIGMS NIH HHS
• P30 AG028718 NIA NIH HHS

Cutaneous inflammation from UV radiation exposure causes epidermal damage, cellular infiltration, and secretion of pro-inflammatory mediators that exacerbate tissue destruction. Recovery is mediated chiefly by anti-inflammatory M2 macrophages that suppress inflammation and augment epidermal regeneration. Vitamin D enables anti-inflammation to promote tissue repair in response to injury. Since vitamin D enhances cellular macroautophagy/autophagy, we investigated the role of autophagy in vitamin D protection of UV-mediated sunburn and inflammation. Using a UV-mediated acute skin injury mouse model, we demonstrate that a single dose of vitamin D resolves injury with sustained inhibition of inflammatory cytokines associated with enhanced autophagy in myeloid anti-inflammatory M2 macs. Increased MAP1LC3B/LC3 expression corroborated with complete autolysosome formation detected by electron microscopy and correlated with degradation of SQSTM1/p62 in the skin following vitamin D treatment. Specifically, pharmacological inhibition of autophagy increased UV-induced apoptosis, suppressed M2 macs recruitment, and prevented vitamin D downregulation of Tnf and Mmp9 in the skin. Furthermore, selective deletion of autophagy in myeloid cells of atg7 cKO mice abrogated vitamin D-mediated protection and recapitulated UV-induced inflammation. Mechanistically, vitamin D signaling activated M2-autophagy regulators Klf4, Pparg, and Arg1. Lastly, analysis of UV-exposed human skin biopsies detected a similar increase in macrophage autophagy following vitamin D intervention, identifying an essential role for autophagy in vitamin D-mediated protection of skin from UV damage.

Abbreviations: ARG1: arginase 1; ATG7 cKO: autophagy related 7 conditional knockout; HPF: high powered field; KLF4: Kruppel like factor 4; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; macs: macrophage; 3-MA: 3-methyladenine; MMP9: matrix metallopeptidase 9; NOS2: nitric oxide synthase 2, inducible; PPARG: peroxisome proliferator activated receptor gamma; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; UV: ultraviolet; VD: vitamin D, 25-hydroxy vitamin D₃; 1,25-VD: 1, 25-dihydroxy vitamin D₃

• Autophagy
• UV
• inflammation
• macrophage
• vitamin D

The aim of the present study was to characterize the roles of two microRNAs (miRNAs), miR-122 and miR-199, in oral lichen planus (OLP). miRNA microarray analysis was performed to detect potential miRNAs involved in OLP, while in-silicon analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemistry (IHC) analyses were utilized to explore the molecular mechanisms underlying the roles of miR-199 and miR-122 in OLP. The results from the microarray and RT-qPCR analyses demonstrated that the expression levels of miR-122 and miR-199 were significantly decreased in the peripheral blood mononuclear cells (PBMCs) collected from the OLP group compared with the control group. In addition, miR-122 and miR-199 directly targeted AKT serine/threonine kinase 1 (AKT1) and mammalian target of rapamycin (mTOR), respectively, by binding to their 3′ UTRs. AKT1 and mTOR were highly expressed in PBMCs derived from OLP patients. In fact, a negative regulatory relationship was observed between miR-122 and AKT1, and between miR-199 and mTOR, with negative correlation coefficients of −0.41 and −0.51, respectively. Furthermore, the protein levels of AKT1, mTOR and microtubule associated protein 1 light chain 3β (LC3B) were upregulated in the OLP group compared with the control group. Finally, overexpression of miR-122 inhibited the expression of AKT1 and LC3B, while overexpression of miR-199 reduced the levels of mTOR and LC3B. In conclusion, the present study demonstrated that miR-199 and miR-122 are implicated in the pathogenesis of OLP by regulating the expression of mTOR and AKT1.

• Autophagy
• Fusion protein
• Hemagglutinin-neuraminidase protein
• Newcastle disease virus

• Autophagy
• Calreticulin
• HMGB1
• HSPs
• NLRs
• PRRs
• RAGE
• RLRs
• TLRs
• cGAS-STING

• Autophagy
• Dengue virus
• Flaviviridae
• Hepatitis C virus
• Japanese encephalitis virus
• West Nile virus
• Zika virus
• selective autophagy

• Animals
• Autophagy/physiology
• Dengue Virus/pathogenicity
• Encephalitis Virus, Japanese/pathogenicity
• Flavivirus/pathogenicity
• Hepacivirus/pathogenicity
• Host-Pathogen Interactions
• Humans
• Zika Virus/pathogenicity

Antiviral restriction factors are host cellular proteins that constitute a first line of defense blocking viral replication and propagation. In addition to interfering at critical steps of the viral replication cycle, some restriction factors also act as innate sensors triggering innate responses against infections. Accumulating evidence suggests an additional role for restriction factors in promoting antiviral cellular immunity to combat viruses. Here, we review the recent progress in our understanding on how restriction factors, particularly APOBEC3G, SAMHD1, Tetherin, and TRIM5α have the cell-autonomous potential to induce cellular resistance against HIV-1 while promoting antiviral innate and adaptive immune responses. Also, we provide an overview of how these restriction factors may connect with protein degradation pathways to modulate anti-HIV-1 cellular immune responses, and we summarize the potential of restriction factors-based therapeutics. This review brings a global perspective on the influence of restrictions factors in intrinsic, innate, and also adaptive antiviral immunity opening up novel research avenues for therapeutic strategies in the fields of drug discovery, gene therapy, and vaccines to control viral infections.

• HIV-1
• adaptive immunity
• degradation pathways
• immunotherapies
• innate immunity
• restriction factors
• virus

• AMP-activated protein kinase (AMPK)
• Autophagy
• Gingival sulcus
• Keratinocytes
• Lipopolysaccharide
• Porphyromonas gingivalis
• Reactive oxygen species (ROS)
• Toll-like receptors (TLRs)

Hypoxia in tumors is known to trigger the pro-survival pathways such as autophagy. Systemic proopiomelanocortin (POMC) gene therapy suppresses melanoma through apoptosis induction and neovascularization blockage. In this study, we investigated the crosstalk between autophagic and apoptotic signaling in POMC-mediated melanoma suppression. By histological and immunoblot analysis, it was shown that POMC-treated melanoma tissues exhibited the prominent LC3 immunostaining, which was correlated with reduced CD31-positive tumor vascularization. Such autophagy induction could be recapitulated in melanoma cells receiving POMC gene delivery and hypoxia-mimicking agent cobalt chloride (CoCl₂). We then utilized the POMC-derived peptide α-MSH with CoCl₂ to elicit the autophagy as well as apoptosis in cultured melanoma cells. To delineate the role of autophagy during cell death, application of autophagy-inducer rapamycin enhanced, whereas autophagy inhibitor 3-MA attenuated, the α-MSH-induced apoptosis in melanoma cells. Genetic silencing of ATG5, an autophagy regulator, by RNA interference perturbed the α-MSH-induced apoptosis in melanoma cells. Finally, it was delineated that α-MSH stimulated the HIF-1α signaling as well as the expression of BNIP3/BNIP3L, thereby promoting the autophagy and apoptosis in melanoma cells. Therefore, the present study unveiled a unique function of autophagy in promoting cell death during POMC-mediated melanoma suppression via α-MSH/HIF-1α/BNIP3/BNIP3L signaling pathway.

Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo, induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B⁺ CD45⁺ cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions.

• TLR2
• autophagy
• inflammation
• myeloid cells
• peptidoglycan
• phosphatidyl-inositol-3 kinase inhibitors

• IL-12p70
• IRF8
• LPS/IFNγ
• SLAMF5
• TRIM21
• autophagy
• dendritic cell