Innate Immune Function Research Articles

Effect of exogenous IL-37 on immune cells from a patient carrying a potential IL37 loss-of-function variant: A case study.

Chronic inflammatory or autoimmune diseases are commonly treated with immunosuppressive medication such as NSAIDs, corticosteroids, or antibodies against specific cytokines (TNF, IL-1 IL-17, IL-23, etc.) or signalling cascades (e.g. JAK-STAT inhibitors). Using sequencing data to locate genetic mutations in relevant genes allows the identification of alternative targets in a patient-tailored therapy setting. Interleukin (IL)-37 is an anti-inflammatory cytokine with broad effects on innate and adaptive immune cell function. Dysfunctional IL-37 expression or signalling is linked to various autoinflammatory disorders. The administration of recombinant IL-37 to hyperinflammatory patients that are non-responsive to standard treatment bears the potential to alleviate symptoms. In this case study, the (hyper)responsiveness of immune cell subsets was investigated in a single patient with a seronegative autoimmune disorder who carries a heterozygous stop-gain variant in IL37 (IL37 Chr2(GRCh37):g.113670640G>A NM_014439.3:c.51G>A p.(Trp17*)). As the patient has been non-responsive to blockage of TNF or IL-1 by Etanercept or Anakinra, respectively, additional in-vitro experiments were set out to elucidate whether treatment with recombinant IL-37 could normalise observed immune cell functions. Characterisation of immune cell function showed no elevated overall production of acute-phase pro-inflammatory cytokines by patient PBMCs and neutrophils at baseline or upon stimulation. T-cell responses were elevated, as was the metabolic activity and IL-1Ra production of PBMCs at baseline. The identified stop-gain variant in IL37 does not result in the absence of the protein in circulation. In line with this, treatment with recombinant IL-37 did overall not dampen immune responses with the exception of the complete suppression of IL-17. The heterozygous stop-gain variant in IL37 (IL37 NM_014439.3:c.51G>A p.(Trp17*)) is not of functional relevance as we observed no clear pro-inflammatory phenotype in immune cells of a patient carrying this variant.

Recovery of constitutive immune function after migratory endurance flight in free-living birds.

Strenuous physical activity can negatively affect constitutive innate immune function (CIF), the always present first line of defence against pathogens. CIF is non-specific, and thus vital when encountering novel pathogens. A lowered CIF likely increases the risk of infection and disease. Migratory birds engage in truly extreme physical activity during their endurance flights, however, little is known about how they deal with the negative impact this has on their immune function. By collecting both between- and within-individual data we show, for the first time, that free-flying migratory birds can recover several parameters of CIF during stopovers, which are stationary periods in between migratory flights. With this, we provide an important piece of the puzzle on how migrating birds cope with the physiological challenges they face on their biannual journeys. Furthermore, our study stresses the importance of migratory stopovers beyond fuel accumulation.

Computational modeling of cyanobacterial phytoconstituents against toll-like receptors of skin cancer

Melanoma is an extremely dangerous disease. The diagnosis and treatment of it may be difficult because of its diversity and complexity. More than 90% of the marine biomass (microflora and microalgae) constitutes the natural biodiversity reserves. TLR-related research developments indicate possible cancer therapeutic possibilities. In addition to its significant function in innate immunity, TLR activation is connected to the start of pyroptosis, apoptosis, or autophagy in malignance cells. For these reasons, TLR agonists are appealing candidates for the production of cancer medications. From the web databases, the ternary structures of the receptors (TLR3 and TLR4) and ligands are extracted. Sixty-nine compounds were subjected to a drug likeness filter, but only twenty-two were screened further for evaluating ADMET criteria, in which only seven compounds satisfied the pharmacological properties. These compounds are further analyzed for docking parameters against TLRs (TLR3 and TLR4) and molecular simulation investigation of the best cluster to evaluate the complex stability. Molecular docking methodology discovered that Scytonmein has a significant binding potential energy of −5.21 and −7.92 kcal/mol against TLR3 and TLR4, respectively, in comparison to the redock co-crystal structure (−3.98 and −4.30 kcal/mol, respectively). The simulation analysis demonstrates the significant stability of the Scytonemin and TLR4 complexes in terms of average RMSD and RMSF compared to the redock complex, while criteria like solvent-accessible surface area (SASA), gyration (Rg) and hydrogen bonding have further supported the significant interaction and stability of the conformations. Communicated by Ramaswamy H. Sarma

Photoperiodic modulation of melatonin receptor and immune genes in migratory redheaded bunting

The transcriptional regulation of innate immune function across annual life history states (LHS) remains obscure in avian migrants. We, therefore, investigated this in a migratory passerine songbird, redheaded bunting (Emberiza bruniceps), which exhibits long-distance vernal migration from India to Central Asia. We exposed the birds (N = 10) to differential photoperiodic conditions to induce a non-migratory (NM), pre-migratory (PM), migratory (MIG), and refractory (REF) state, and performed gene expression assays of melatonin receptors (MEL1A and MEL1B), and innate immunity-linked genes (IL1B, IL6, TLR4, and NFKB) in spleen and blood. We found a significant reduction in splenic mass and volume, and a parallel increase in fat accumulation, and testicular growth in birds under migratory state. The gene expression assay revealed an upregulation of MEL1A and MEL1B mRNA levels in both the tissues in MIG. Additionally, we found a nocturnal increase of splenic IL1B expression, and IL1B, IL6, and TLR4 expression in the blood. The mRNA expression of melatonin receptors and proinflammatory cytokine showed a positive correlation. These results suggest that melatonin relays the photoperiodic signal to peripheral immune organs, which shows LHS-dependent changes in mRNA expression of immune genes.

A novel l-rhamnose-binding lectin participates in defending against bacterial infection in zebrafish

l-rhamnose-binding lectin (RBL), which is a class of animal lectins independent of Ca2+, can specifically bind l-rhamnose or d-galactose. Although several lectins in zebrafish have been reported, their functional mechanisms have not been fully uncovered. In this study, we discovered a novel l-rhamnose binding lectin (DrRBL) and studied its innate immune function. The DrRBL protein contains only one carbohydrate-recognition domain (CRD), which includes two strictly conserved motifs, “YGR” and “DPC”. DrRBL was detected in all tested tissues and was present at high levels in the spleen, hepatopancreas and skin. After Aeromonas hydrophila challenge, the DrRBL mRNA level was significantly upregulated. Additionally, DrRBL was secreted into the extracellular matrix. Recombinant DrRBL (rDrRBL) could significantly inhibit the growth of gram-positive/negative bacteria, bind to several bacteria and cause obvious agglutination. The rDrRBL protein could combine with polysaccharides, such as PGN and LPS, rather than LTA. A more detailed study showed that rDrRBL could combine with monosaccharides, such as mannose, rhamnose and glucose, which are important components of PGN and LPS. However, rDrRBL could not bind to ribitol, which is an important component of LTA. The DrRBL deletion mutants, DrRBLΔ144-150 and DrRBLΔ198-200, were also constructed. DrRBLΔ144-150 (“ANYGRTD” deficient) showed weak bacterial inhibiting ability. However, DrRBLΔ198-200 (“DPC” deficient) showed weak agglutination ability. These results suggest that the “DPC” domain is important for agglutination. The conserved domain “ANYGRTD” is essential for inhibiting bacterial growth.

Molecular characterization of two newly identified glycine rich crustin genes (Mn-Gly-Cru3, Mn-Gly-Cru4) and their function in Macrobrachium nipponense innate immunity

Crustin, as an important antibacterial peptide in crustacean, plays a role in the defense against the invasion of foreign pathogens in the innate immune system. In this study, two glycine rich crustin genes (named as Mn-Gly-Cru3 and Mn-Gly-Cru4) were cloned in Macrobrachium nipponense. The full-length cDNA of Mn-Gly-Cru3 and Mn-Gly-Cru4 were 740 and 781 bp with open reading frames of 525 and 576 bp that encode 174 and 191 amino acids, respectively. The genome structure of Mn-Gly-Cru3 and Mn-Gly-Cru4 shows that both contain two exons and one intron. Both Mn-Gly-Cru3 and Mn-Gly-Cru4 protein contains a signal peptide, a cysteine-rich region, a glycine-rich region, and a whey acidic protein domain. Evolutionary analysis showed that Mn-Gly-Cru1, Mn-Gly-Cru2, Mn-Gly-Cru3 and Mn-Gly-Cru4 were clustered together. Mn-Gly-Cru3 and Mn-Gly-Cru4 were widely distributed in multiple tissues. After white spot syndrome virus (WSSV), Staphylococcus aureus or Vibrio parahaemolyticus challenge, the expression levels of Mn-Gly-Cru3 and Mn-Gly-Cru4 in the hemocytes, gills, and stomach were significantly changed. Mn-Gly-Cru3 and Mn-Gly-Cru4 knockdown remarkably increased the copy number of WSSV and the number of S. aureus and V. parahaemolyticus colonies in vivo. Purified rMn-Gly-Cru3 and rMn-Gly-Cru4 proteins could bind to a variety of bacteria and they also had binding activity toward LPS or PGN. Furthermore, rMn-Gly-Cru4 had a stronger binding activity to polysaccharides than rMn-Gly-Cru3. Our study indicates that Mn-Gly-Cru3 and Mn-Gly-Cru4 in M. nipponense are involved in the innate immune defense against bacteria or viruses.

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways.

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.

Interleukin-18 and IL-18BP in inflammatory dermatological diseases.

Interleukin (IL)-18, an interferon-γ inducer, belongs to the IL-1 family of pleiotropic pro-inflammatory factors, and IL-18 binding protein (IL-18BP) is a native antagonist of IL-18 in vivo, regulating its activity. Moreover, IL-18 exerts an influential function in host innate and adaptive immunity, and IL-18BP has elevated levels of interferon-γ in diverse cells, suggesting that IL-18BP is a negative feedback inhibitor of IL-18-mediated immunity. Similar to IL-1β, the IL-18 cytokine is produced as an indolent precursor that requires further processing into an active cytokine by caspase-1 and mediating downstream signaling pathways through MyD88. IL-18 has been implicated to play a role in psoriasis, atopic dermatitis, rosacea, and bullous pemphigoid in human inflammatory skin diseases. Currently, IL-18BP is less explored in treating inflammatory skin diseases, while IL-18BP is being tested in clinical trials for other diseases. Thereby, IL-18BP is a prospective therapeutic target.

Current Understanding of DDX41 Mutations in Myeloid Neoplasms.

The DEAD-box RNA helicase 41 gene, DDX41, is frequently mutated in hereditary myeloid neoplasms, identified in 2% of entire patients with AML/MDS. The pathogenesis of DDX41 mutation is related to the defect in the gene's normal functions of RNA and innate immunity. About 80% of patients with germline DDX41 mutations have somatic mutations in another allele, resulting in the biallelic DDX41 mutation. Patients with the disease with DDX41 mutations reportedly often present with the higher-grade disease, but there are conflicting reports about its impact on survival outcomes. Recent studies using larger cohorts reported a favorable outcome with a better response to standard therapies in patients with DDX41 mutations to patients without DDX41 mutations. For stem-cell transplantation, it is important for patients with DDX41 germline mutations to identify family donors early to improve outcomes. Still, there is a gap in knowledge on whether germline DDX41 mutations and its pathology features can be targetable for treatment, and what constitutes an appropriate screening/surveillance strategy for identified carriers. This article reviews our current understanding of DDX41 mutations in myeloid neoplasms in pathologic and clinical features and their clinical implications.

Temporal dynamics of the bat wing transcriptome: Insight into gene-expression changes that enable protection against pathogen

ABSTRACT Skin acts as a mechanical barrier between the body and its surrounding environment and plays an important role in resistance to pathogens. However, we still know little regarding skin responses to physiological changes, particularly with regard to responses against potential pathogens. We herein executed RNA-seq on the wing of the Rhinolophus ferrumequinum to assess gene-expression variations at four physiological stages: pre-hibernation, hibernation (early-hibernation and late-hibernation), and post-hibernation, as well as the gene-expression patterns of infected and uninfected bats with the Pseudogymnoascus destructans (Pd). Our results showed that a greater number of differentially expressed genes between the more disparate physiological stages. Functional enrichment analysis showed that the down-regulated response pathways in hibernating bats included phosphorus metabolism and immune response, indicating metabolic suppression and decreased whole immune function. We also found up-regulated genes in post-hibernating bats that included C-type lectin receptor signalling, Toll-like receptor signalling pathway, and cell adhesion, suggesting that the immune response and skin integrity of the wing were improved after bats emerged from their hibernation and that this facilitated clearing Pd from the integument. Additionally, we found that the genes involved in cytokine or chemokine activity were up-regulated in late-hibernation compared to early-hibernation and that FOSB regulation of immune cell activation was differentially expressed in bats infected with Pd during late-hibernation, implying that the host’s innate immune function was enhanced during late-hibernation so as to resist pathogenic infection. Our findings highlight the concept that maintenance of intrinsic immunity provides protection against pathogenic infections in highly resistant bats.

Osthole Antagonizes Microglial Activation in an NRF2-Dependent Manner

Microglia are neuroglia in the brain with an innate immune function and participate in the progress of neurodegenerative diseases. Osthole (OST) is a coumarin derivative extracted from Cnidium monnieri and bears a microglia-antagonizing ability. However, the underlying mechanism of the antagonism is not clear. The lipopolysaccharides-induced microglial BV2 cell line and amyloid-overexpressing fruit fly were used as models to study OST treatment. We found that OST treatment is sufficient to evoke NRF2 cascade under an LPS-induced inflammatory environment, and silencing NRF2 is sufficient to abolish the process. Moreover, we found that OST is sufficient to antagonize microglial activation in both LPS-induced BV2 cells and Aβ-overexpressing fruit flies, and silencing NRF2 abolishes OST's antagonism. Furthermore, OST treatment rescued survival, climbing, and the learning ability of Aβ-overexpressing fruit flies and relieved oxidative stress. In conclusion, we proved that OST antagonizes microglial activation induced by either LPS or Aβ and that NRF2 is necessary for OST's antagonism.

Cellular and humoral factors of innate antiviral immunity

The study presents new data on the biological effects of well-known cellular and humoral factors that ensure the functioning of innate immunity. Four mechanisms induced by viruses, which lead to the destruction of inhibitory proteins and trigger the transcription of interferon genes, are described. The paper also presented the order of synthesis of species of interferons and other pro-inflammatory cytokines in the development of an antiviral immune response. This is of great importance because viruses have significantly different resistance to the biological effects of interferons. Interferon lambda played a role in the development of innate immune reactions against many viruses, and the effectiveness of the functioning of the mechanisms of the innate and adaptive immunity in viral infections was evaluated, depending on the state of the stat l, 4, 6 genes and genes of interferon regulators. An interferon-independent variant of the innate immune response in viral infections that occurs a few hours after infection and is associated with chemokine CXCL10 has been described. Data on the most important role of the ubiquitin-proteasome cleavage pathway of proteins and the complement system in the implementation of antiviral effects of innate immunity are also presented. The uniqueness of the microbicidal effects of natural killers, which are realized only in cells that reduced the expression of major histocompatibility complex I molecules, has been established. In addition, natural killers can recognize and do not attack target cells carrying antigens of HLA-E, the sublocus of the major histocompatibility complex I molecules. The natural killers were found to acquire the properties of memory cells. This is facilitated by interleukins 12 and 18. The extracellular neutrophil traps of neutrophils showed microbicidal effects against many viruses. The congenital lymphoid cells have multifaceted effects on the development of an antiviral immune response.

Plant-oriented microbiome inoculum modulates age-related maturation of gut-mucosal expression of innate immune and barrier function genes in suckling and weaned piglets.

In the immediate time after weaning, piglets often show symptoms of gut inflammation. The change to a plant-based diet, lack of sow milk, and the resulting novel gut microbiome and metabolite profile in digesta may be causative factors for the observed inflammation. We used the intestinal loop perfusion assay (ILPA) to investigate jejunal and colonic expression of genes for antimicrobial secretion, oxidative stress, barrier function, and inflammatory signaling in suckling and weaned piglets when exposed to "plant-oriented" microbiome (POM) representing postweaning digesta with gut-site specific microbial and metabolite composition. Two serial ILPA were performed in two replicate batches, with 16 piglets preweaning (days 24 to 27) and 16 piglets postweaning (days 38 to 41). Two jejunal and colonic loops were perfused with Krebs-Henseleit buffer (control) or with the respective POM for 2 h. Afterward, RNA was isolated from the loop tissue to determine the relative gene expression. Age-related effects in jejunum included higher expression of genes for antimicrobial secretions and barrier function as well as reduced expression of pattern-recognition receptors post- compared to preweaning (P < 0.05). Age-related effects in the colon comprised downregulation of the expression of pattern-recognition receptors post- compared to preweaning (P < 0.05). Likewise, age reduced the colonic expression of genes encoding for cytokines, antimicrobial secretions, antioxidant enzymes, and tight-junction proteins post- compared to preweaning. Effect of POM in the jejunum comprised an increased the expression of toll-like receptors compared to the control (P < 0.05), demonstrating a specific response to microbial antigens. Similarly, POM administration upregulated the jejunal expression of antioxidant enzymes (P < 0.05). The POM perfusion strongly upregulated the colonic expression of cytokines and altered the expression of barrier function genes, fatty acid receptors and transporters, and antimicrobial secretions (P < 0.05). In conclusion, results indicated that POM signaled via altering the expression of pattern-recognition receptors in the jejunum, which in turn activated the secretory defense and decreased mucosal permeability. In the colon, POM may have acted pro-inflammatory via upregulated cytokine expression. Results are valuable for the formulation of transition feeds for the immediate time after weaning to maintain mucosal immune tolerance towards the novel digesta composition.

The endoplasmic reticulum stress sensor IRE1α modulates macrophage metabolic function during Brucella abortus infection.

Endoplasmic reticulum (ER) stress plays a major role in several inflammatory disorders. ER stress induces the unfolded protein response (UPR), a conserved response broadly associated with innate immunity and cell metabolic function in various scenarios. Brucella abortus, an intracellular pathogen, triggers the UPR via Stimulator of interferon genes (STING), an important regulator of macrophage metabolism during B. abortus infection. However, whether ER stress pathways underlie macrophage metabolic function during B. abortus infection remains to be elucidated. Here, we showed that the UPR sensor inositol-requiring enzyme 1α (IRE1α) is as an important component regulating macrophage immunometabolic function. In B. abortus infection, IRE1α supports the macrophage inflammatory profile, favoring M1-like macrophages. IRE1α drives the macrophage metabolic reprogramming in infected macrophages, contributing to the reduced oxidative phosphorylation and increased glycolysis. This metabolic reprogramming is probably associated with the IRE1α-dependent expression and stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), an important molecule involved in cell metabolism that sustains the inflammatory profile in B. abortus-infected macrophages. Accordingly, we demonstrated that IRE1α favors the generation of mitochondrial reactive oxygen species (mROS) which has been described as an HIF-1α stabilizing factor. Furthermore, in infected macrophages, IRE1α drives the production of nitric oxide and the release of IL-1β. Collectively, these data unravel a key mechanism linking the UPR and the immunometabolic regulation of macrophages in Brucella infection and highlight IRE1α as a central pathway regulating macrophage metabolic function during infectious diseases.

Role of γδ T Lymphocytes in the Pathogenesis of Autoimmune Diseases with Skin Lesions

Autoimmune diseases are associated with a severe course, early complications, disability and early mortality. Subpopulations of γδ T cells participate in the development of autoimmune diseases, including experimental ones, contributing to tissue damage. The inflammatory functions of γδ T cells are determined by their synthesis of cytokines, including IL-17, IFNγ and TNF-α, which are usually involved in autoimmunity. Different subpopulations of γδ T cells are associated with different autoimmune diseases depending on their tissue expression, and their function may contribute to pathogenesis. In this article we review studies on the role of γδ T cells in autoimmune diseases such as rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, and scleroderma, as well as their animal models. Due to the unique properties of γδ T cells encompassing adaptive and innate immunity functions, a growing understanding of this unique T cell population sheds new light on the pathogenesis of these diseases and potentially allows new therapeutic approaches to their treatment.

Changes in expression levels of Nod-like receptors in the spleen of ewes.

Nucleotide-binding oligomerization domain receptors (NOD-like receptors, NLRs) have critical effects on interfaces of the immune and reproductive systems, and the spleen plays a key role in both innate and adaptive immune functions. It is hypothesized that NLR family participates in maternal splenic immune regulation during early pregnancy in sheep. In this study, maternal spleens were collected on day 16 of the estrous cycle, and days 13, 16 and 25 of gestation (n = 6 for each group) in ewes. Expression of NLR family, including NOD1, NOD2, class II transactivator (CIITA), NLR family apoptosis inhibitory protein (NAIP), nucleotide-binding oligomerization domain, Leucine rich repeat and Pyrin domain containing 1 (NLRP1), NLRP3 and NLRP7, was analyzed using quantitative real-time PCR, Western blot and immunohistochemistry analysis. The results revealed that expression levels of NOD1, NOD2, CIITA and NLRP3 were downregulated at days 13 and 16 of pregnancy, but expression of NLRP3 was increased at day 25 of pregnancy. In addition, expression values of NAIP and NLRP7 mRNA and proteins were improved at days 16 and 25 of pregnancy, and NLRP1 was peaked at days 13 and 16 of pregnancy in the maternal spleen. Furthermore, NOD2 and NLRP7 proteins were limited to the capsule, trabeculae and splenic cords. In summary, early pregnancy changes expression of NLR family in the maternal spleen, which may be related with the maternal splenic immunomodulation during early pregnancy in sheep.

Aquaporins in Immune System.

Recent studies have shown that at least six aquaporins (AQPs), including AQP1, AQP3, AQP4, AQP5, AQP7, and AQP9, are expressed in immune system. These AQPs distribute in lymphocytes, macrophages, dendritic cells, and neutrophils, and mediate water and glycerol transportation in these cells, which play important roles in innate and adaptive immune functions. Immune system plays important roles in body physiological functions and health. Therefore, understanding the association between AQPs and immune system may provide approaches to prevent and treat related diseases. Here we will discuss the expression and physiological functions of AQPs in immune system and summarize recent researches on AQPs in immune diseases.

Tuning innate immune function using microneedles containing multiple classes of toll-like receptor agonists.

Microneedle arrays (MNAs) are patches displaying hundreds of micron-scale needles that can penetrate skin. As a result, these arrays efficiently and painlessly access this immune cell-rich niche, motivating significant clinical interest in MNA-based vaccines. Our lab has developed immune polyelectrolyte multilayers (iPEMs), nanostructures built entirely from immune signals employing electrostatic self-assembly. iPEMs consist of positively charged peptide antigen and negatively charged toll-like receptor agonists (TLRas) to assemble these components at ultra-high density since no carrier is needed. Here we used this technology to deliver MNAs with antigen and defined ratios of multiple classes of TLRa. Notably, this approach resulted in facile assembly and corresponding signal transduction through each respective TLR pathway. This control ultimately activated primary antigen presenting cells and drove proliferation of antigen-specific T cells. In related in vivo vaccine studies, application of MNAs resulted in distinct T cells response depending on the number of TLRa classes delivered with MNAs. These MNAs technologies create an opportunity to deliver nanostructured vaccine components at high density, and to probe integration of multiple TLRas in skin to tune immunity.

Advanced Glycation End Products-Induced Activation of Keratinocytes: A Mechanism Underlying Cutaneous Immune Response in Psoriasis

Psoriasis is a common inflammatory skin disease, in which epidermal keratinocytes play a vital role in its pathogenesis by acting both as the responder and as the accelerator to the cutaneous psoriatic immune response. Advanced glycation end products (AGEs) are a class of proinflammatory metabolites that are commonly accumulating in cardiometabolic disorders. Recent studies have also observed the increased level of AGEs in the serum and skin of psoriasis patients, but the role of AGEs in psoriatic inflammation has not been well investigated. In the present study, we initially detected abnormal accumulation of AGEs in epidermal keratinocytes of psoriatic lesions collected from psoriasis patients. Furthermore, AGEs promoted the proliferation of keratinocytes via upregulated Keratin 17 (K17)-mediated p27KIP1 inhibition followed by accelerated cell cycle progression. More importantly, AGEs facilitated the production of interleukin-36 alpha (IL-36α) in keratinocytes, which could enhance T helper 17 (Th17) immune response. In addition, the induction of both K17 and IL-36α by AGEs in keratinocytes was dependent on the activation of signal transducer and activator of transcription 1/3 (STAT1/3) signaling pathways. At last, the effects of AGEs on keratinocytes were mediated by the receptor for AGEs (RAGE). Taken together, these findings support that AGEs potentiate the innate immune function of keratinocytes, which contributes to the formation of psoriatic inflammation. Our study implicates AGEs as a potential pathogenic link between psoriasis and cardiometabolic comorbidities.

Gingival transcriptomic patterns of macrophage polarization during initiation, progression, and resolution of periodontitis.

Phenotypic and functional heterogeneity of macrophages is clearly a critical component of their effective functions in innate and adaptive immunity. This investigation hypothesized that altered profiles of gene expression in gingival tissues in health, disease, and resolution would reflect changes in macrophage phenotypes occurring in these tissues. The study used a nonhuman primate model to evaluate gene expression profiles as footprints of macrophage variation using a longitudinal experimental model of ligature-induced periodontitis in animals from 3 to 23 years of age to identify aging effects on the gingival environment. Significant differences were observed in distribution of expressed gene levels for M0, M1, and M2 macrophages in healthy tissues with the younger animals showing the least expression. M0 gene expression increased with disease in all but the aged group, while M1 was increased in adult and young animals, and M2 in all age groups, as early as disease initiation (within 0.5 months). Numerous histocompatibility genes were increased with disease, except in the aged samples. An array of cytokines/chemokines representing both M1 and M2 cells were increased with disease showing substantial increases with disease initiation (e.g. IL1A, CXCL8, CCL19, CCL2, CCL18), although the aged tissues showed a more limited magnitude of change across these macrophage genes. The analytics of macrophage genes at sites of gingival health, disease, and resolution demonstrated distinct profiles of host response interactions that may help model the disease mechanisms occurring with the formation of a periodontal lesion.