Regulation Of Innate Immune Responses Research Articles

Current insights into apolipoprotein E and the immune response in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological disorder and the most common cause of dementia. Genetic analyses identified apolipoprotein E (APOE) as the strongest genetic risk for late-onset AD. Studies have shown that ApoE modulates AD pathogenesis in part by influencing amyloid-β (Aβ) deposition. However, ApoE also appears to regulate elements of AD via regulation of innate immune response, especially through microglial and astrocyte activation. In model systems, it also regulates changes in T-cells. This review focuses on the key findings that have advanced our understanding of the role of ApoE in the pathogenesis of AD and the current view of innate immune response regulated by ApoE in AD, while discussing open questions and areas for future research.

Both host and parasite non-coding RNAs co-ordinate the regulation of macrophage gene expression to reduce pro-inflammatory immune responses and promote tissue repair pathways during infection with fasciola hepatica

ABSTRACT Parasitic worms (helminths) establish chronic infection within mammalian hosts by strategically regulating their host’s immune responses. Deciphering the mechanisms by which host non-coding RNAs (ncRNA) co-ordinate the activation and regulation of immune cells is essential to understanding host immunity and immune-related pathology. It is also important to comprehend how pathogens secrete specific ncRNAs to manipulate gene expression of host immune cells and influence their response to infection. To investigate the contribution of both host and helminth derived ncRNAs to the activation and/or regulation of innate immune responses during a parasite infection, we examined ncRNA expression in the peritoneal macrophages from mice infected with Fasciola hepatica. We discovered the presence of several parasitic-derived miRNAs within host macrophages at 6 hrs and 18 hrs post infection. Target prediction analysis showed that these Fasciola miRNAs regulate host genes associated with the activation of host pro-inflammatory macrophages. Concomitantly, there was a distinct shift in host ncRNA expression, which was significant at 5 days post-infection. Prediction analysis suggested that these host ncRNAs target a different cohort of host genes compared to the parasite miRNAs, although the functional outcome was predicted to be similar i.e. reduced pro-inflammatory response and the promotion of a reparative/tolerant phenotype. Taken together, these observations uncover the interplay between host and parasitic ncRNAs and reveal a complementary regulation of the immune response that allows the parasite to evade immune detection and promote tissue repair for the host. These findings will provide a new understanding of the molecular interaction between parasites and host.

Bioactive components in prunella vulgaris for treating Hashimoto's disease via regulation of innate immune response in human thyrocytes

BackgroundHashimoto's thyroiditis (HT) is a thyroid autoimmune disease characterized by lymphocytic infiltration and thyroid destruction. Prunella vulgaris (PV) is a traditional Chinese herbal medicine with documented clinical efficacy in treating HT. We previously reported an immunoregulatory effect of PV in thyrocytes; however, the bioactive components of PV remained unclear. This study aimed to elucidate key components of PV for treating HT and their acting mechanisms. MethodsNetwork pharmacology was used to predict key PV components for HT. The predicted components were tested to determine whether they could exert an immunoregulatory effect of PV in human thyrocytes. Limited proteolysis-mass spectrometry (Lip-MS) was used to explore interacting proteins with PV components in human thyrocytes. Microscale thermophoresis binding assay was used to evaluate the affinity of PV components with the target protein. ResultsEleven PV components with 192 component targets and 3415 HT-related genes were gathered from public databases. With network pharmacology, a ‘component-target-disease’ network was established wherein four flavonoids including quercetin, luteolin, kaempferol, morin, and a phytosterol, β-sitosterol were predicted as key components in PV for HT. In stimulated primary human thyrocytes or Nthy-ori-31 cells, key components inhibited gene expressions of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interferon-β (IFN-β), cellular apoptosis, and activation of nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF-3). Heat shock protein 90 alpha, class A, member 1 (HSP90AA1), was identified to interact with flavonoids in PV by Lip-MS. Morin had the highest affinity with HSP90AA1 (KD = 122.74 μM), followed by kaempferol (KD = 168.53 μM), luteolin (KD = 293.94 μM), and quercetin (KD = 356.86 μM). ConclusionQuercetin, luteolin, kaempferol, morin, and β-sitosterol reproduced an anti-inflammatory and anti-apoptosis effect of PV in stimulated human thyrocytes, which potentially contributed to the treatment efficacy of PV in HT.

Comparative transcriptomics identifies genes underlying growth performance of the Pacific black-lipped pearl oyster Pinctada margaritifera

BackgroundIn bivalves, the rate at which organisms grow is a major functional trait underlying many aspects of their commercial production. Growth is a highly polygenic trait, which is typically regulated by many genes with small to moderate effects. Due to its complexity, growth variability in such shellfish remains poorly understood. In this study, we aimed to investigate differential gene expression among spat of the pearl oyster Pinctada margaritifera with distinct growth phenotypes.ResultsWe selected two groups of P. margaritifera spat belonging to the same F2 cohort based on their growth performance at 5.5 months old. Transcriptome profile analysis identified a total of 394 differentially expressed genes between these Fast-growing (F) and Slow-growing (S) phenotypes. According to functional enrichment analysis, S oysters overexpressed genes associated with stress-pathways and regulation of innate immune responses. In contrast, F oysters up-regulated genes associated with cytoskeleton activity, cell proliferation, and apoptosis. Analysis of genome polymorphism identified 16 single nucleotide polymorphisms (SNPs) significantly associated with the growth phenotypes. SNP effect categorization revealed one SNP identified for high effect and annotated for a stop codon gained mutation. Interestingly, this SNP is located within a gene annotated for scavenger receptor class F member 1 (SRF1), which is known to modulate apoptosis. Our analyses also revealed that all F oysters showed up-regulation for this gene and were homozygous for the stop-codon mutation. Conversely, S oysters had a heterozygous genotype and a reduced expression of this gene.ConclusionsAltogether, our findings suggest that differences in growth among the same oyster cohort may be explained by contrasted metabolic allocation between regulatory pathways for growth and the immune system. This study provides a valuable contribution towards our understanding of the molecular components associated with growth performance in the pearl oyster P. margaritifera and bivalves in general.

Identification of COMMD gene family in large yellow croaker (Larimichthys crocea): Immune response induced by Pseudomonas plecoglossicida infection and acute hypoxia stress

The COMMD (Copper Metabolism gene MURR1 Domain) gene family consists of 10 members, which are involved in various biological processes such as copper and sodium transport, NF-κB activity and cell cycle progression. However, the study of COMMD gene family in large yellow croaker (Larimichthys crocea) is largely unknown. In this study, 10 COMMD gene family members (named LcCOMMDs) were successfully identified from large yellow croaker. The results showed that there were differences in the number of LcCOMMDs exons at the level of gene structure, which reflected that they had adjusted and changed accordingly in the process of evolution to adapt to the environment and achieved functional diversification. Through phylogenetic analysis, we found that the LcCOMMDs was highly conserved, indicating their important functions in organisms. It was worth noting that the expression levels of LcCOMMD1, LcCOMMD2, LcCOMMD3, LcCOMMD5 and LcCOMMD10 in the spleen changed significantly after bacterial stress, which suggested that these genes might be involved in the regulation of innate immune response. In addition, the expression levels of LcCOMMD1, LcCOMMD2, LcCOMMD3, LcCOMMD5, LcCOMMD7, LcCOMMD8, LcCOMMD9 and LcCOMMD10 changed significantly after hypoxia exposure, which further proved the role of LcCOMMDs in immune function. In summary, this study not only revealed the important role of COMMD genes in the innate immune response of large yellow croaker, but also provided valuable information for further understanding the regulatory mechanism of COMMD gene family under different conditions.

Neonatal and maternal upregulation of antileukoproteinase in horses.

The end of gestation, ensuing parturition, and the neonatal period represent highly dynamic phases for immunological changes in both mother and offspring. The regulation of innate immune cells at the maternal-fetal interface during late term pregnancy, after birth, and during microbial colonization of the neonatal gut and other mucosal surfaces, is crucial for controlling inflammation and maintaining homeostasis. Innate immune cells and mucosal epithelial cells express antileukoproteinase (SLPI), which has anti-inflammatory and anti-protease activity that can regulate cellular activation. Here, we developed and validated new monoclonal antibodies (mAbs) to characterize SLPI for the first time in horses. Peripheral blood and mucosal samples were collected from healthy adults horses and a cohort of mares and their foals directly following parturition to assess this crucial stage. First, we defined the cell types producing SLPI in peripheral blood by flow cytometry, highlighting the neutrophils and a subset of the CD14+ monocytes as SLPI secreting immune cells. A fluorescent bead-based assay was developed with the new SLPI mAbs and used to establish baseline concentrations for secreted SLPI in serum and secretion samples from mucosal surfaces, including saliva, nasal secretion, colostrum, and milk. This demonstrated constitutive secretion of SLPI in a variety of equine tissues, including high colostrum concentrations. Using immunofluorescence, we identified production of SLPI in mucosal tissue. Finally, longitudinal sampling of clinically healthy mares and foals allowed monitoring of serum SLPI concentrations. In neonates and postpartum mares, SLPI peaked on the day of parturition, with mares returning to the adult normal within a week and foals maintaining significantly higher SLPI secretion until three months of age. This demonstrated a physiological systemic change in SLPI in both mares and their foals, particularly at the time around birth, likely contributing to the regulation of innate immune responses during this critical period.

The landscape of rare genetic variants in familial Waldenström macroglobulinemia

AbstractWaldenström macroglobulinemia (WM) is a rare hematological malignancy. Risk for WM is elevated 20-fold among first-degree relatives of patients with WM. However, the list of variants and genes that cause WM remains incomplete. In this study we analyzed exomes from 64 WM pedigrees for evidence of genetic susceptibility for this malignancy. We determined the frequency of pathogenic (P) or likely pathogenic (LP) variants among patients with WM; performed variant- and gene-level association analyses with the set of 166 WM cases and 681 unaffected controls; and examined the segregation pattern of deleterious variants among affected members in each pedigree. We identified P/LP variants in TREX1 and SAMHD1 (genes that function at the interface between innate immune response, genotoxic surveillance, and DNA repair) segregating in patients with WM from 2 pedigrees. There were additional P/LP variants in cancer-predisposing genes (eg, POT1, RECQL4, PTPN11, PMS2). In variant- and gene-level analyses, no associations were statistically significant after multiple testing correction. On a pathway level, we observed involvement of genes that play a role in telomere maintenance (q-value = 0.02), regulation of innate immune response (q-value = 0.05), and DNA repair (q-value = 0.08). Affected members of each pedigree shared multiple deleterious variants (median, n = 18), but the overlap between the families was modest. In summary, P/LP variants in highly penetrant genes constitute a modest proportion of the deleterious variants; each pedigree is largely unique in its genetic architecture, and multiple genes are likely involved in the etiology of WM.

Comprehensive analysis and validation reveal DEPDC1 as a potential diagnostic biomarker associated with tumor immunity in non-small-cell lung cancer.

Current evidence suggests that DEP domain containing 1 (DEPDC1) has an important effect on non-small-cell lung cancer (NSCLC). However, the diagnostic value and the regulatory function within NSCLC are largely unclear. This work utilized publicly available databases and in vitro experiments for exploring, DEPDC1 expression, clinical features, diagnostic significance and latent molecular mechanism within NSCLC. According to our results, DEPDC1 was remarkably upregulated in the tissues of NSCLC patients compared with non-carcinoma tissues, linked with gender, stage, T classification and N classification based on TCGA data and associated with smoking status and stage according to GEO datasets. Meanwhile, the summary receiver operating characteristic (sROC) curve analysis result showed that DEPDC1 had a high diagnostic value in NSCLC (AUC = 0.96, 95% CI: 0.94-0.98; diagnostic odds ratio = 99.08, 95%CI: 31.91-307.65; sensitivity = 0.89, 95%CI: 0.81-0.94; specificity = 0.92, 95%CI: 0.86-0.96; positive predictive value = 0.94, 95%CI: 0.89-0.98; negative predictive value = 0.78, 95%CI: 0.67-0.90; positive likelihood ratio = 11.77, 95%CI: 6.11-22.68; and negative likelihood ratio = 0.12, 95%CI: 0.06-0.22). Subsequently, quantitative real-time PCR (qRT-PCR) and western blotting indicated that DEPDC1 was high expressed in NSCLC cells. According to the in vitro MTS and apoptotic assays, downregulated DEPDC1 expression targeting P53 signaling pathway inhibited the proliferation of NSCLC cells while promoting apoptosis of NSCLC cells. Moreover, DEPDC1 was significantly correlated with immune cell infiltrating levels in NSCLC based on TCGA data, which were primarily associated with T cells CD4 memory activated, macrophages M1, B cells memory, mast cells resting, T cells regulatory, monocytes, and T cells CD4 memory resting. Compared with the group with high expression of DEPDC1, the group with low expression level had higher scores for immune checkpoint inhibitors (ICIs) treatment. GSEA confirmed that DEPDC1 was involved in gene expression and tumor-related signaling pathways. Finally, DEPDC1 and its associated immune-related genes were shown to be enriched in 'receptor ligand activity', 'external side of plasma membrane', 'regulation of innate immune response', and 'Epstein-Barr virus infection' pathways. The present study demonstrates that DEPDC1 may contribute to NSCLC tumorigenesis and can be applied as the biomarker for diagnosis and immunology.

Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells.

Seoul orthohantavirus (SEOV) is a rat-borne zoonotic virus that is transmitted via inhalation of aerosolized infectious excreta, and can cause hemorrhagic fever with renal syndrome (HFRS) in humans worldwide. In rats, SEOV predominantly exists as a persistent infection in the absence of overt clinical signs. Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses. As lung microvascular endothelial cells (LMECs) represent a primary target of infection in both human and rats, infections in these cells provide a unique opportunity to study the central role of LMECs in the dichotomy between pathogenicity in both species. In this study, host responses to SEOV infection in primary human and rat LMECs were directly compared on a transcriptional level. As infection of rat LMECs was more efficient than human LMECs, the majority of anti-viral defense responses were observed earlier in rat LMECs. Most prominently, SEOV-induced processes in both species included responses to cytokine stimulus, negative regulation of innate immune responses, responses to type I and II interferons, regulation of pattern recognition receptor signaling and MHC-I signaling. However, over time, in the rat LMECs, responses shifted from an anti-viral state towards a more immunotolerant state displayed by a PD-L1, B2M-, JAK2-focused interaction network aiding in negative regulation of cytotoxic CD8-positive T cell activation. This suggests a novel mechanism by which species-specific orthohantavirus-induced endothelium and T cell crosstalk may play a crucial role in the development of acute disease in humans and persistence in rodents.

Foot-and-mouth disease virus VP1 degrades YTHDF2 through autophagy to regulate IRF3 activity for viral replication

ABSTRACT Many viruses, including foot-and-mouth disease virus (FMDV), can promote the degradation of host proteins through macroautophagy/autophagy, thereby promoting viral replication. However, the regulatory mechanism between autophagy and innate immune responses is not fully understood during FMDV infection. Here, we found that the host GTPBP4/NOG1 (GTP binding protein 4) is a negative regulator of innate immune responses. GTPBP4 deficiency promotes the antiviral innate immune response, resulting in the ability of GTPBP4 to promote FMDV replication. Meanwhile, GTPBP4-deficient mice are more resistant to FMDV infection. To antagonize the host’s antiviral immunity, FMDV structural protein VP1 promotes the expression of GTPBP4, and the 209th site of VP1 is responsible for this effect. Mechanically, FMDV VP1 promotes autophagy during virus infection and interacts with and degrades YTHDF2 (YTH N6-methyladenosine RNA binding protein F2) in an AKT-MTOR-dependent autophagy pathway, resulting in an increase in GTPBP4 mRNA and protein levels. Increased GTPBP4 inhibits IRF3 binding to the Ifnb/Ifn-β promoter, suppressing FMDV-induced type I interferon production. In conclusion, our study revealed an underlying mechanism of how VP1 negatively regulates innate immunity through the autophagy pathway, which would contribute to understanding the negative regulation of host innate immune responses and the function of GTPBP4 and YTHDF2 during FMDV infection. Abbreviation: 3-MA:3-methyladenine; ACTB: actin beta; ATG: autophagy related; ChIP:chromatin immunoprecipitation; CQ: chloroquine; DAPI:4’,6-diamidino-2-phenylindole; dpi: days post-infection; EV71:enterovirus 71; FMDV: foot-and-mouth disease virus; GTPBP4/NOG1: GTPbinding protein 4; HIF1A: hypoxia inducible factor 1 subunit alpha;hpt:hours post-transfection; IFNB/IFN-β:interferon beta; IRF3: interferon regulatory factor 3; MAP1LC3/LC3:microtubule associated protein 1 light chain 3; MAVS: mitochondriaantiviral signaling protein; MOI: multiplicity of infection; MTOR:mechanistic target of rapamycin kinase; m6A: N(6)-methyladenosine;qPCR:quantitativePCR; SIRT3:sirtuin 3; SQSTM1/p62: sequestosome 1; STING1: stimulator ofinterferon response cGAMP interactor 1; siRNA: small interfering RNA;TBK1: TANK binding kinase 1; TCID50:50% tissue culture infectious doses; ULK1: unc-51 like autophagyactivating kinase 1; UTR: untranslated region; WT: wild type; YTHDF2:YTH N6-methyladenosine RNA binding protein F2

Bile acid metabolites enhance expression of cathelicidin antimicrobial peptide in airway epithelium through activation of the TGR5-ERK1/2 pathway

Signals for the maintenance of epithelial homeostasis are provided in part by commensal bacteria metabolites, that promote tissue homeostasis in the gut and remote organs as microbiota metabolites enter the bloodstream. In our study, we investigated the effects of bile acid metabolites, 3-oxolithocholic acid (3-oxoLCA), alloisolithocholic acid (AILCA) and isolithocholic acid (ILCA) produced from lithocholic acid (LCA) by microbiota, on the regulation of innate immune responses connected to the expression of host defense peptide cathelicidin in lung epithelial cells. The bile acid metabolites enhanced expression of cathelicidin at low concentrations in human bronchial epithelial cell line BCi-NS1.1 and primary bronchial/tracheal cells (HBEpC), indicating physiological relevance for modulation of innate immunity in airway epithelium by bile acid metabolites. Our study concentrated on deciphering signaling pathways regulating expression of human cathelicidin, revealing that LCA and 3-oxoLCA activate the surface G protein-coupled bile acid receptor 1 (TGR5, Takeda-G-protein-receptor-5)—extracellular signal-regulated kinase (ERK1/2) cascade, rather than the nuclear receptors, aryl hydrocarbon receptor, farnesoid X receptor and vitamin D3 receptor in bronchial epithelium. Overall, our study provides new insights into the modulation of innate immune responses by microbiota bile acid metabolites in the gut-lung axis, highlighting the differences in epithelial responses between different tissues.

A2M possesses anti-bacterial functions by recruiting and enhancing phagocytosis through GRP78 in an echinoderm

Alpha-2-macroglobulin (A2M) is an extracellular macromolecule mainly known for its role as a broad-spectrum protease inhibitor in mammals. However, the immune recognition and regulation mechanisms of A2M in invertebrates are still not well investigated. In the current study, the role of sea cucumber Apostichopus japonicus A2M in the regulation of innate immune responses was explored. We found that AjA2M promotes phagocytosis of Vibrio splendidus in coelomocytes of sea cucumber. Then two major functional structural domains of AjA2M, the thioester domain (TED) and the receptor-binding structural domain (RBD) were cloned. It was found that the AjA2M-TED binds to pathogens while causing Vibrio splendidus aggregation; the AjA2M-RBD interacts with the Glucose Regulated Protein 78 (AjGRP78), subsequently AjGRP78 accelerates the degradation of Vibrio splendidus in lysosomes by facilitating polymerisation and rearrangement of the cytoskeleton. Collectively, the findings together suggest that A2M-GRP78 axis mediates immune signaling pathway of phagocytosis and AjA2M has been characterized to play an essential crucial role in antibacterial immune responses of invertebrates.

TF-FVIIa PAR2-β-Arrestin Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection of Mice.

Accumulating evidence implicates the activation of G-protein-coupled PARs (protease-activated receptors) by coagulation proteases in the regulation of innate immune responses. Using mouse models with genetic alterations of the PAR2 signaling platform, we have explored contributions of PAR2 signaling to infection with coxsackievirus B3, a single-stranded RNA virus provoking multiorgan tissue damage, including the heart. We show that PAR2 activation sustains correlates of severe morbidity-hemodynamic compromise, aggravated hypothermia, and hypoglycemia-despite intact control of the virus. Following acute viral liver injury, canonical PAR2 signaling impairs the restoration process associated with exaggerated type I IFN (interferon) signatures in response to viral RNA recognition. Metabolic profiling in combination with proteomics of liver tissue shows PAR2-dependent reprogramming of liver metabolism, increased lipid droplet storage, and gluconeogenesis. PAR2-sustained hypodynamic compromise, reprograming of liver metabolism, as well as imbalanced IFN responses are prevented in β-arrestin coupling-deficient PAR2 C-terminal phosphorylation mutant mice. Thus, wiring between upstream proteases and immune-metabolic responses results from biased PAR2 signaling mediated by intracellular recruitment of β-arrestin. Importantly, blockade of the TF (tissue factor)-FVIIa (coagulation factor VIIa) complex capable of PAR2 proteolysis with the NAPc2 (nematode anticoagulant protein c2) mitigated virus-triggered pathology, recapitulating effects seen in protease cleavage-resistant PAR2 mice. These data provide insights into a TF-FVIIa signaling axis through PAR2-β-arrestin coupling that is a regulator of inflammation-triggered tissue repair and hemodynamic compromise in coxsackievirus B3 infection and can potentially be targeted with selective coagulation inhibitors.

Systems genetics of influenza A virus-infected mice identifies TRIM21 as a critical regulator of pulmonary innate immune response

Tripartite motif 21 (TRIM21) is a cytosolic Fc receptor that targets antibody-bound, internalized pathogens for destruction. Apart from this intrinsic defense role, TRIM21 is implicated in autoimmune diseases, inflammation, and autophagy. Whether TRIM21 participates in host interactions with influenza A virus (IAV), however, is unknown. By computational modeling of body weight and lung transcriptome data from the BXD parents (C57BL/6 J (B6) and DBA/2 J (D2)) and 41 BXD mouse strains challenged by IAV, we reveal that a Trim21-associated gene network modulates the early host responses to IAV infection. Trim21 transcripts were significantly upregulated in infected mice of both B6 and D2 backgrounds. Its expression was significantly higher in infected D2 than in infected B6 early after infection and significantly correlated with body weight loss. We identified significant trans-eQTL on chromosome 14 that regulates Trim21 expression. Nr1d2 and Il3ra were among the strongest candidate genes. Pathway analysis found Trim21 to be involved in inflammation and immunity related pathways, such as inflammation signaling pathways (TNF, IL-17, and NF-κB), viral detection signaling pathways (NOD-like and RIG-I-like), influenza, and other respiratory viral infections. Knockdown of TRIM21 in human lung epithelial A549 cells significantly augmented IAV-induced expression of IFNB1, IFNL1, CCL5, CXCL10, and IFN-stimulated genes including DDX58 and IFIH1, among others. Our data suggest that a TRIM21-associated gene network is involved in several aspects of inflammation and viral detection mechanisms during IAV infection. We identify and validate TRIM21 as a critical regulator of innate immune responses to IAV in human lung epithelial cells.

The Identification Distinct Antiviral Factors Regulated Influenza Pandemic H1N1 Infection.

Influenza pandemic with H1N1 (H1N1pdms) causes severe lung damage and "cytokine storm," leading to higher mortality and global health emergencies in humans and animals. Explaining host antiviral molecular mechanisms in response to H1N1pdms is important for the development of novel therapies. In this study, we organised and analysed multimicroarray data for mouse lungs infected with different H1N1pdm and nonpandemic H1N1 strains. We found that H1N1pdms infection resulted in a large proportion of differentially expressed genes (DEGs) in the infected lungs compared with normal lungs, and the number of DEGs increased markedly with the time of infection. In addition, we found that different H1N1pdm strains induced similarly innate immune responses and the identified DEGs during H1N1pdms infection were functionally concentrated in defence response to virus, cytokine-mediated signalling pathway, regulation of innate immune response, and response to interferon. Moreover, comparing with nonpandemic H1N1, we identified ten distinct DEGs (AREG, CXCL13, GATM, GPR171, IFI35, IFI47, IFIT3, ORM1, RETNLA, and UBD), which were enriched in immune response and cell surface receptor signalling pathway as well as interacted with immune response-related dysregulated genes during H1N1pdms. Our discoveries will provide comprehensive insights into host responding to pandemic with influenza H1N1 and find broad-spectrum effective treatment.

RNA m5C methylation: a potential modulator of innate immune pathways in hepatocellular carcinoma.

RNA 5-methylcytosine (m5C) methylation plays a crucial role in hepatocellular carcinoma (HCC). As reported, aberrant m5C methylation is closely associated with the progression, therapeutic efficacy, and prognosis of HCC. The innate immune system functions as the primary defense mechanism in the body against pathogenic infections and tumors since it can activate innate immune pathways through pattern recognition receptors to exert anti-infection and anti-tumor effects. Recently, m5C methylation has been demonstrated to affect the activation of innate immune pathways including TLR, cGAS-STING, and RIG-I pathways by modulating RNA function, unveiling new mechanisms underlying the regulation of innate immune responses by tumor cells. However, research on m5C methylation and its interplay with innate immune pathways is still in its infancy. Therefore, this review details the biological significance of RNA m5C methylation in HCC and discusses its potential regulatory relationship with TLR, cGAS-STING, and RIG-I pathways, thereby providing fresh insights into the role of RNA methylation in the innate immune mechanisms and treatment of HCC.

Molecular characterization and functional study of a galectin-9 from a teleost fish, Boleophthalmus pectinirostris

Galectin-9, a tandem-repeat galectin, plays an important role in the regulation of innate immune response against various microbial infections. Here, galectin-9 from mudskipper (Boleophthalmus pectinirostris) was identified and named as BpGal-9. Putative BpGal-9 contains two conserved carbohydrate recognition domains (CRDs), one CRD within N-terminal (N-CRD) and the other one within C-terminal (C-CRD). Multi-alignment analysis indicated that BpGal-9 shared the highest amino acid sequence identity of 64.3 % with that of Southern platyfish (Xiphophorus maculatus). Phylogenetic analysis showed that BpGal-9 grouped tightly with other teleosts galectin-9 and was most closely related to that of Southern platyfish. BpGal-9 transcripts were more abundant in the intestine, and its expression upregulated significantly in the intestine, kidney, spleen, gills, and skin after Edwardsiella tarda infection. Meanwhile, BpGal-9 expression significantly increased in hemocytes and serum of mudskipper infected by E. tarda. The recombinant BpGal-9 (rBpGal-9) and rBpGal-9C-CRD could agglutinate all tested bacteria, whereas rBpGal-9N-CRD could only agglutinate three kinds of bacteria. When targeting the same bacteria, rBpGal-9 showed stronger agglutinating activities than rBpGal-9C-CRD or rBpGal-9N-CRD. In addition, the induction effect of three recombinant proteins on the mRNA expression of anti-inflammatory cytokines (BpIL-10 and BpTGF-β) was better than that on the pro-inflammatory cytokines (BpIL-1β and BpTNF-α). Our result suggested that the N-CRD and C-CRD of galectin-9 contribute differently to its multiple functions in innate immunity in teleosts.

Regulation of Mitochondrial Metabolism by Hepatitis B Virus.

Mitochondria play important roles in the synthesis of ATP, the production of reactive oxygen species, and the regulation of innate immune response and apoptosis. Many viruses perturb mitochondrial activities to promote their replication and cause cell damage. Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). This virus can also alter mitochondrial functions and metabolism to promote its replication and persistence. In this report, we summarize recent research progress on the interaction between HBV and mitochondrial metabolism, as well as the effect this interaction has on HBV replication and persistence.

Sex-dimorphic expression of extracellular matrix genes in mouse bone marrow neutrophils.

The mammalian innate immune system is sex-dimorphic. Neutrophils are the most abundant leukocyte in humans and represent innate immunity's first line of defense. We previously found that primary mouse bone marrow neutrophils show widespread sex-dimorphism throughout life, including at the transcriptional level. Extracellular matrix [ECM]-related terms were observed among the top sex-dimorphic genes. Since the ECM is emerging as an important regulator of innate immune responses, we sought to further investigate the transcriptomic profile of primary mouse bone marrow neutrophils at both the bulk and single-cell level to understand how biological sex may influence ECM component expression in neutrophils throughout life. Here, using curated gene lists of ECM components and unbiased weighted gene co-expression network analysis [WGCNA], we find that multiple ECM-related gene sets show widespread female-bias in expression in primary mouse neutrophils. Since many immune-related diseases (e.g., rheumatoid arthritis) are more prevalent in females, our work may provide insights into the pathogenesis of sex-dimorphic inflammatory diseases.

A Macrophage-Related Gene Signature for Identifying COPD Based on Bioinformatics and ex vivo Experiments.

This study aims to investigate the association between immune cells and the development of COPD, while providing a new method for the diagnosis of COPD according to the changes in immune microenvironment. In this study, the "CIBERSORT" algorithm was used to estimate the tissue infiltration of 22 types of immune cells in GSE20257 and GSE10006. The "limma" package was used for differentially expressed analysis. The key modules associated with vital immune cells were identified using WGCNA. GO and KEGG enrichment analysis revealed the biological functions of the candidate genes. Ultimately, a novel diagnostic prediction model was constructed via machine learning methods and multivariate logistic regression analysis based on GSE20257. Furthermore, we examined the stability of the model on one internal test set (GSE10006), three external test sets (GSE8545, GSE57148 and GSE76925), one single-cell transcriptome dataset (GSE167295), macrophages (THP-M cells) and lung tissue from COPD patients. M0 macrophages (AUC > 0.7 in GSE20257 and GSE10006) were considered as the most important immune cells through exploring the immune microenvironment landscapes in COPD patients and healthy controls. The differentially expressed genes from GSE20257 and GSE10006 were divided into six and five modules via WGCNA, respectively. The green module in GSE20257 (cor = 0.41, P < 0.001) and the brown module in GSE10006 (cor = 0.67, P < 0.001) were highly correlated with M0 macrophages and were selected as key modules. Forty-one intersected genes obtained from two modules were primarily involved in regulation of cytokine production, regulation of innate immune response, specific granule, phagosome, lysosome, ferroptosis, and other biological processes. On the basis of the candidate genetic markers further characterized via the "Boruta" and "LASSO" algorithm for COPD, a diagnostic model comprising CLEC5A, FTL and SLC2A3 was constructed, which could accurately distinguish COPD patients from healthy controls in multiple datasets. GSE20257 as the training set has an AUC of 0.916. The AUCs of the internal test set and three external test sets were 0.873, 0.932, 0.675 and 0.688, respectively. Single-cell sequencing analysis suggested that CLEC5A, FTL and SLC2A3 were expressed in macrophages from COPD patients. The expressions of CLEC5A, FTL and SLC2A3 were up-regulated in THP-M cells and lung tissue from COPD patients. According to the variations of immune microenvironment in COPD patients, we constructed and validated a novel macrophage M0-associated diagnostic model with satisfactory predictive value. CLEC5A, FTL and SLC2A3 are expected to be promising targets of immunotherapy in COPD.