Activation Of Innate Immune Cells Research Articles

Natural killer like B cells are a distinct but infrequent innate immune cell subset modulated by SIV infection of rhesus macaques.

Natural killer-like B (NKB) cells are unique innate immune cells expressing both natural killer (NK) and B cell receptors. As first responders to infection, they secrete IL-18 to induce a critical cascade of innate and adaptive immune cell infiltration and activation. However, limited research exists on the role of NKB cells in homeostasis and infection, largely due to incomplete and erroneous evaluations. To fill this knowledge gap, we investigated the expression of signaling and trafficking proteins, and the in situ localization and transcriptome of naïve NKB cells comparied to conventionally-defined NK and B cells, as well as modulations of these cells in SIV infection. Intracellular signaling proteins and trafficking markers were expressed differentially on naïve NKB cells, with high expression of CD62L and Syk, and low expression of CD69, α4β7, FcRg, Zap70, and CD3z, findings which were more similar to B cells than NK cells. CD20+NKG2a/c+ NKB cells were identified in spleen, mesenteric lymph nodes (MLN), colon, jejunum, and liver of naïve rhesus macaques (RM) via tissue imaging, with NKB cell counts concentrated in spleen and MLN. For the first time, single cell RNA sequencing (scRNAseq), including BCR sequencing, of sorted NKB cells confirmed that NKB cells are unique. Transcriptomic analysis of naïve splenic NKB cells by scRNAseq showed that NKB cells undergo somatic hypermutation and express Ig receptors, similar to B cells. While only 15% of sorted NKB cells showed transcript expression of both KLRC1 (NKG2A) and MS4A1 (CD20) genes, only 5% of cells expressed KLRC1, MS4A1, and IgH/IgL transcripts. We observed expanded NKB frequencies in RM gut and buccal mucosa as early as 14 and 35 days post-SIV infection, respectively. Further, mucosal and peripheral NKB cells were associated with colorectal cytokine mileu and oral microbiome changes, respectively. Our studies indicate that NKB cells gated on CD3-CD14-CD20+NKG2A/C+ cells were inclusive of transcriptomically conventional B and NK cells in addition to true NKB cells, confounding accurate phenotyping and frequency recordings that could only be resolved using genomic techniques. Although NKB cells were clearly elevated during SIV infection and associated with inflammatory changes during infection, further interrogation is necessary to acurately identify the true phenotype and significance of NKB cells in infection and inflammation.

Deletion of codY impairs Staphylococcus epidermidis biofilm formation, generation of viable but non-culturable cells and stimulates cytokine production in human macrophages.

Introduction. Staphylococcus epidermidis biofilms are one of the major causes of bloodstream infections related to the use of medical devices. The diagnosis of these infections is challenging, delaying their treatment and resulting in increased morbidity and mortality rates. As such, it is urgent to characterize the mechanisms employed by this bacterium to endure antibiotic treatments and the response of the host immune system, to develop more effective therapeutic strategies. In several bacterial species, the gene codY was shown to encode a protein that regulates the expression of genes involved in biofilm formation and immune evasion. Additionally, in a previous study, our group generated evidence indicating that codY is involved in the emergence of viable but non-culturable (VBNC) cells in S. epidermidis.Gap statement/Hypothesis. As such, we hypothesized that the gene codY has have an important role in this bacterium virulence.Aim. This study aimed to assess, for the first time, the impact of the deletion of the gene codY in S. epidermidis virulence, namely, in antibiotic susceptibility, biofilm formation, VBNC state emergence and in vitro host immune system response.Methodology. Using an allelic replacement strategy, we constructed and then characterized an S. epidermidis strain lacking codY, in regards to biofilm and VBNC cell formation, susceptibility to antibiotics as well as their role in the interaction with human blood and plasma. Additionally, we investigate whether the codY gene can impact the activation of innate immune cells by evaluating the production of both pro- and anti-inflammatory cytokines by THP-1 macrophages.Results. We demonstrated that the deletion of the gene codY resulted in biofilms with less c.f.u. counts and fewer VBNC cells. Furthermore, we show that although WT and mutant cells were similarly internalized in vitro by human macrophages, a stronger cytokine response was elicited by the mutant in a toll-like receptor 4-dependent manner.Conclusion. Our results indicate that codY contributes to S. epidermidis virulence, which in turn may have an impact on our ability to manage the biofilm-associated infections caused by this bacterium.

Canonical and non-canonical roles of complement in atherosclerosis.

Cardiovascular diseases are the leading cause of death globally, and atherosclerosis is the major contributor to the development and progression of cardiovascular diseases. Immune responses have a central role in the pathogenesis of atherosclerosis, with the complement system being an acknowledged contributor. Chronic activation of liver-derived and serum-circulating canonical complement sustains endothelial inflammation and innate immune cell activation, and deposition of complement activation fragments on inflamed endothelial cells is a hallmark of atherosclerotic plaques. However, increasing evidence indicates that liver-independent, cell-autonomous and non-canonical complement activities are underappreciated contributors to atherosclerosis. Furthermore, complement activation can also have atheroprotective properties. These specific detrimental or beneficial contributions of the complement systemto the pathogenesis of atherosclerosis are dictated by the location of complement activation and engagement of its canonical versus non-canonical functions in a temporal fashion during atherosclerosis progression. In this Review, we summarize the classical and the emerging non-classical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential strategies for therapeutic modulation of complement for the prevention and treatment of atherosclerotic cardiovascular disease.

Abstract CT078: Phase 1 study of SGN-EGFRd2 in solid tumors (SGNEGFRd2-001)

Abstract Background: Epidermal growth factor receptor (EGFR) is a cell surface receptor expressed in a variety of solid tumors. Gamma delta (γδ)-T cells represent a conserved T cell subset that can induce cell death in a wide range of malignancies. The presence of γ9δ2-T cells in solid tumors strongly correlates with better patient survival (Gentles 2015; Tosolini 2017). In addition to direct, potent killing by release of cytotoxic molecules, activated γ9δ2-T cells process and present antigen and contribute to a cascade response resulting in downstream activation of innate and adaptive immune cells to mediate further tumor cell killing (Brandes 2005; Devilder 2006; Vantourout 2013). Novel approaches that improve targeting and activation of γ9δ2-T cells may lead to the development of effective and safe cancer treatments. SGN-EGFRd2 is an investigational, bispecific humanized heavy chain-only antibody (HcAb). Advantages of HcAbs include their small size, high solubility, high stability, and excellent tissue penetration in vivo (Bannas 2017). SGN-EGFRd2 simultaneously binds EGFR and the γ9δ2-T cell receptor, resulting in the conditional activation of γ9δ2-T cells. Importantly, full activation of γ9δ2-T cells requires a secondary phosphoantigen stress signal present only in malignant and certain infected cells (Deseke 2020; Herrmann 2020; Rigau 2020; Vantourout 2013), but not normal healthy cells, conferring preferential tumor-directed cytotoxicity. The proposed cytotoxic mechanism of action is independent of KRAS and BRAF mutations (King 2023) known to confer resistance to approved anti-EGFR therapies in colorectal cancer (CRC). This first-in-human study is evaluating the safety, tolerability, and antitumor activity of SGN-EGFRd2 in patients with advanced solid tumors. Methods: SGNEGFRd2-001 (NCT05983133) is an open-label, multicenter, phase 1, dose escalation and expansion study evaluating SGN-EGFRd2 monotherapy in patients with relapsed/refractory (R/R) CRC, head and neck squamous cell cancer, non-small cell lung cancer, and pancreatic ductal adenocarcinoma in 3 parts: dose escalation (Part A; n ~ 75), dose optimization (Part B; optional; up to n = 40), and dose expansion (Part C; up to n = 160). Patients must have R/R disease, or be intolerant to standard of care therapies, with no appropriate standard therapy available. Patients must have measurable disease per RECIST v1.1, an ECOG performance status of 0 or 1, and adequate organ function. Patients are eligible regardless of tumor EGFR expression or EGFR/KRAS/BRAF mutation status. Patients will receive SGN-EGFRd2 as an intravenous infusion. Primary study objectives are safety and tolerability, maximum tolerated dose, and recommended dose and schedule. Secondary objectives include pharmacokinetics, immunogenicity, and antitumor activity. Tumor samples will be analyzed for exploratory biomarkers. Accrual is ongoing in the US. Additional sites in Europe and Canada are planned. Citation Format: Hirva Mamdani, Joel Randolph Hecht, Rachel E. Sanborn, Maria Corinna Palanca-Wessels, Mingjin Yan, Martin Gutierrez, David L. Bajor. Phase 1 study of SGN-EGFRd2 in solid tumors (SGNEGFRd2-001) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT078.

Skeletal muscle of young females under resistance exercise exhibits a unique innate immune cell infiltration profile compared to males and elderly individuals.

Muscle damage resulting from physical activities such as exercise triggers an immune response crucial for tissue repair and recovery. This study investigates the immune cell profiles in muscle biopsies of individuals engaged in resistance exercise (RE) and explores the impact of age and sex on the immune response following exercise-induced muscle damage. Microarray datasets from muscle biopsies of young and old subjects were analyzed, focusing on the gene expression patterns associated with immune cell activation. Genes were compared with immune cell signatures to reveal the cellular landscape during exercise. Results show that the most significant modulated gene after RE was Folliculin Interacting Protein 2 (FNIP2) a crucial regulator in cellular homeostasis. Moreover, the transcriptome was stratified based on the expression of FNIP2 and the 203 genes common to the groups obtained based on sex and age. Gene ontology analysis highlighted the FLCN-FNIP1-FNIP2 complex, which exerts as a negative feedback loop to Pi3k-Akt-mTORC1 pathway. Furthermore, we highlighted that the young females exhibit a distinct innate immune cell activation signature compared to males after a RE session. Specifically, young females demonstrate a notable overlap with dendritic cells (DCs), M1 macrophages, M2 macrophages, and neutrophils, while young males overlap with M1 macrophages, M2 macrophages, and motor neurons. Interestingly, in elderly subjects, both sexes display M1 macrophage activation signatures. Comparison of young and elderly signatures reveals an increased M1 macrophage percentage in young subjects. Additionally, common genes were identified in both sexes across different age groups, elucidating biological functions related to cell remodeling and immune activation. This study underscores the intricate interplay between sex, age, and the immune response in muscle tissue following RE, offering potential directions for future research. Nevertheless, there is a need for further studies to delve deeper and confirm the dynamics of immune cells in response to exercise-induced muscle damage.

Senescent fibroblasts and innate immune cell activation might play a role in the pathogenesis of elderly atopic dermatitis

BackgroundElderly atopic dermatitis (AD) is a subtype of AD defined by age (≥60 years). The molecular characteristics of elderly AD remain to be clarified. ObjectiveWe sought to characterize the molecular features of skin lesions and peripheral blood mononuclear cells (PBMCs) in patients with AD across different age, focusing on elderly AD. MethodsSkin and PBMCs samples were used for RNA sequencing. Analysis of differentially expressed genes and gene set variation analysis were performed. Immunofluorescence staining, quantitative real-time PCR (qRT-PCR), flow cytometry and transwell assay were used for validation. ResultsCompared with healthy controls, the skin transcriptome of AD patients showed common signatures of AD, like barrier dysfunction and enhanced Th1/Th2/Th17 immune pathways. In PBMCs, the expression of Th1/Th2 response genes was more remarkable in adult AD, while expression of Th17-related genes was significantly higher in childhood AD. The gene modules associated with natural killer (NK) cells were downregulated in elderly AD. In skin lesions, elderly AD exhibited enrichment of macrophages, fibroblasts and senescence-associated secretory phenotype (SASP) related genes. The correlation among fibroblasts, SASP and innate immune cells were revealed by the co-localization of fibroblasts, macrophages and NK cells in the lesions across different age groups. Fibroblasts under inflammation or senescence could induce stronger chemotaxis of macrophages and NK cells. ConclusionWe identified the molecular phenotypes of skin lesions and PBMCs in elderly AD individuals. Fibroblasts, innate immune cells, and SASP might play important roles in the pathogenesis of elderly AD.

Abstract 1183: A first-in-class and SHP1 allosteric inhibitor, SB8091, shows a good efficacy and safety profile in preclinical models

Abstract Introduction: Src homology 2 domain-containing phosphatase 1 (SHP1) is a cytoplasmic protein tyrosine phosphatase (PTP) that is primarily expressed in hematopoietic cells and is commonly recognized as a negative regulator of multiple signaling pathways1. Previously, we showed that inhibition of the phosphatase activity of SHP1 by a novel SHP1 allosteric inhibitor, SB6299, results in the activation of innate and adaptive immune cells and enhanced anti-tumor immune responses2. Here, we report SB8091, an advanced SHP1 allosteric inhibitor with a promising initial safety profile and improved pharmacokinetic properties. Methods: SHP1 inhibitors were developed through a structure-based drug design approach, and optimized for cellular activity on target, in vitro ADME, and in vivo pharmacokinetic properties. Pharmacokinetic (PK) and preliminary toxicity studies were performed with mice. The lead series was assessed in in-vitro studies with mouse or human primary immune cells. In-vivo efficacy and pharmacodynamic data were generated using mouse syngeneic tumor models. Results: Structurally, SB8091 seemed to stabilize the autoinhibitory form of SHP1 as an allosteric inhibitor, in a nanomolar range and which can explain the outstanding selectivity compared to other PTP enzymes, including SHP2. In several human primary immune cell types, SB8091 significantly increased cytokine responses and demonstrated significantly enhanced activity in NK cells and macrophages against various cancer target cells. As a single agent, this compound exhibited inhibitory effects on tumor growth when administered orally, and the efficacy was further enhanced when co-administered with anti-PD1 antibodies in various syngeneic tumor models. Notably, this effect was associated with a pharmacodynamic response marked by increased levels of phosphorylated substrates regulated by SHP1. SB8091 exhibited favorable pharmacokinetic properties for oral administration, and SafetyScreen data showed a very low potential for off-target activity and drug-drug interactions. Additionally, during a 2-week repeat pilot toxicity study in mice, SB8091 demonstrated excellent tolerability even at high doses, indicating a high therapeutic index (TI > 100). Conclusion: Our advanced compound, SB8091, is a potent, highly selective, and orally bioavailable allosteric inhibitor of SHP1. It has demonstrated excellent efficacy as a monotherapy or in combination with immune checkpoint blockers, with favorable drug properties and safety profiles. Research to advance to the clinical stage is being conducted.

Abstract 6734: Preclinical impact of pretreatment with CRS mitigation agents on pharmacodynamic response to TAK-500, a systemically delivered CCR2-targeted STING agonist iADC

Abstract Background: Stimulator of interferon genes (STING) agonists elicit potent innate immune enhancement and mobilize robust adaptive immune responses. Given the potential risk of immunotoxicity from associated cytokine release due to STING agonist treatment, there is a need to identify mitigation strategies that minimize immune-related toxicity while offering a therapeutic window for STING-mediated anti-tumor effects. This strategy is particularly relevant for myeloid-targeted immunotherapies, as cytokine release syndrome (CRS) can be myeloid cell-mediated. We utilized preclinical models to evaluate the pharmacological impact of pretreatment with agents routinely used for management of CRS in advance of delivering TAK-500, a novel, systemic, immune-cell directed STING agonist antibody drug conjugate (iADC) that selectively targets CCR2+ myeloid cells. Methods: Dexamethasone and anti-IL-6R antibodies were tested at clinically relevant doses 1 hour prior to treatment with TAK-500 or mTAK-500, a murine surrogate, to study immunomodulatory and anti-tumor effects in preclinical models. Induction of innate and adaptive immune responses and cytokine release was evaluated in human, ex vivo, and in tumor-bearing mouse models to characterize potential impact of premedication strategies on drug pharmacology and anti-tumor efficacy. Results: TAK-500 triggered dose-dependent monocyte activation and cytokine secretion ex vivo. Monocyte activation was minimally impacted by dexamethasone or anti-IL-6R pretreatment. Suppression of IL-6 and IFN-ƴ and increase in IL-10 were observed following dexamethasone pretreatment, whereas anti-IL-6R maintained a more proinflammatory milieu. In syngeneic mouse models, pretreatment with dexamethasone and anti-mouse IL-6R had minimal impact on mTAK-500 anti-tumor efficacy. Key pharmacodynamic effects, including innate immune cell activation in periphery and tumor-draining lymph node and intratumoral CD8+ T cell accumulation, were minimally impacted by either pretreatment agent. Serum cytokine analyses demonstrated suppression of IL-6, IFN-ƴ and increases in IL-10 with dexamethasone, but not with anti-IL-6R, similar to ex vivo findings. Conclusion: Premedication of TAK-500 and mTAK-500 with dexamethasone or anti-IL-6R antibodies does not substantially impact STING-mediated innate immune activation, mobilization of adaptive immune responses or anti-tumor efficacy, despite altered cytokine profiles compared to (m)TAK-500 without premedication. Clinically, these premedication strategies have been effective in mitigating immunotherapy-associated CRS with T cell therapeutics, and here resulted in maintained anti-tumor activity when used in combination with TAK-500, suggesting a viable potential strategy for mitigation of STING-induced immunotoxicities in patients. Citation Format: Emily Rosentrater, Michelle L. Ganno, Tiquella Hatten, Henry Mack, Arjun Reddy Bollampalli, Dong Mei Zhang, Alex Parent, Jeffrey Raizer, Richard C. Gregory, Neil Lineberry, Vicky Appleman. Preclinical impact of pretreatment with CRS mitigation agents on pharmacodynamic response to TAK-500, a systemically delivered CCR2-targeted STING agonist iADC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6734.

Langerhans cells and gamma delta Т-lymphocytes in the pathogenesis of psoriasis

Psoriasis is a frequently occurring inflammatory skin disease. Fundamental research into the pathogenesis of psoriasis has significantly expanded our understanding of skin immunology, which has enabled the introduction of innovative and highly effective therapies. Psoriasis is a largely T-lymphocyte-mediated disease in which activation of innate immune cells and pathogenic T cells leads to inflammation and hyperproliferation of keratinocytes. Langerhans cells like dendritic cells (DCs), which play an important role in the immune system, are mainly distributed in the epidermis. Since human and mouse skin DC subpopulations share common ontogenetic characteristics, we can further investigate the role of DCs in psoriatic inflammation in mice. γδT cells are an unconventional population of T-lymphocytes that play an indispensable role in host defense, immune surveillance, and immune system homeostasis. Although γδT cells constitute only a small fraction of the total T cell pool, emerging evidence suggests that aberrantly activated γδT cells may play a role in the pathogenesis of psoriasis. Dermal γδT cells are the major IL-17-producing cells in the skin that respond to IL-23 stimulation. In addition, γδT cells have characteristics of memory cells that mediate repeated episodes of psoriatic inflammation. This review discusses the mechanisms by which Langerhans cells and γδT cells participate in the pathogenesis of psoriasis.

The Impact of Microbiota-Immunity-Hormone Interactions on Autoimmune Diseases and Infection.

Autoimmune diseases are complex multifactorial disorders, and a mixture of genetic and environmental factors play a role in their onset. In recent years, the microbiota has gained attention as it helps to maintain host health and immune homeostasis and is a relevant player in the interaction between our body and the outside world. Alterations (dysbiosis) in its composition or function have been linked to different pathologies, including autoimmune diseases. Among the different microbiota functions, there is the activation/modulation of immune cells that can protect against infections. However, if dysbiosis occurs, it can compromise the host's ability to protect against pathogens, contributing to the development and progression of autoimmune diseases. In some cases, infections can trigger autoimmune diseases by several mechanisms, including the alteration of gut permeability and the activation of innate immune cells to produce pro-inflammatory cytokines that recruit autoreactive T and B cells. In this complex scenario, we cannot neglect critical hormones' roles in regulating immune responses. Different hormones, especially estrogens, have been shown to influence the development and progression of autoimmune diseases by modulating the activity and function of the immune system in different ways. In this review, we summarized the main mechanisms of connection between infections, microbiota, immunity, and hormones in autoimmune diseases' onset and progression given the influence of some infections and hormone levels on their pathogenesis. In detail, we focused on rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.

Increased cardiovascular risk in patients with chronic kidney disease.

Cardiovascular disease (CVD) is highly prevalent in patients suffering from chronic kidney disease (CKD). The risk of patients with CKD developing CVD is manifested already in the early stages of CKD development. The impact of declined kidney function on increased cardiovascular risk and the underlying mechanisms are complex and multifactorial. This review discusses the impact of (a) traditional cardiovascular risk factors such as smoking, dyslipidemia, diabetes, and hypertension as well as (b) CKD-specific pathophysiological and molecular mechanisms associated with an increased cardiovascular risk. The latter include uremic toxins, post-translational modifications and uremic lipids, innate immune cell activation and inflammation, oxidative stress, endothelial cell dysfunction, increased coagulation and altered platelet responses, vascular calcification, renin-angiotensin-aldosterone-system (RAAS) and sympathetic activation, as well as anemia. Unraveling the complex interplay of different risk factors, especially in the context of patient subcohorts, will help to find new therapeutic approaches in order to reduce the increased cardiovascular risk in this vulnerable patient cohort.

Gene-edited pigs: a translational model for human food allergy against alpha-Gal and anaphylaxis.

The prevalence of food allergy is rising and is estimated to approach 10%. Red meat allergy is the first known food allergy elicited by immunoglobulin E (IgE) antibodies recognizing a carbohydrate. Due to the loss of function of the alpha-1,3-galactosyltransferase (GGTA1) gene in humans, the disaccharide galactose-α-1,3-galactose (α-Gal) cannot be synthesized and therefore became immunogenic. IgE sensitization is elicited through the skin by repetitive tick bites transmitting α-Gal. The underlying mechanisms regarding innate and adaptive immune cell activation, including the B-cell isotype switch to IgE, are poorly understood, requiring further research and physiologically relevant animal models. Here, we describe a new animal model of red meat allergy using percutaneous α-Gal sensitization of gene-edited GGTA1-deficient pigs. Total and α-Gal-specific IgG, IgG1, IgG2, IgG4, and IgE levels were tracked. Further key factors associated with allergic skin inflammation, type 2 immunity, and allergy development were measured in PBMCs and skin samples. Significant increases in α-Gal-specific IgG1 and IgE levels indicated successful sensitization to the allergen α-Gal. Intracutaneous sensitizations with α-Gal recruited lymphocytes to the skin, including elevated numbers of T helper 2 (Th2) cells. Finally, α-Gal-sensitized pigs not only recognized α-Gal as non-self-antigen following α-Gal exposure through the skin but also developed anaphylaxis upon antigen challenge. Based on the similarities between the porcine and human skin, this new large animal model for α-Gal allergy should help to unveil the consecutive steps of cutaneous sensitization and aid the development of prophylactic and treatment interventions.

Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis.

Spotted fever group rickettsiae are tick-borne obligate intracellular bacteria that infect microvascular endothelial cells. Humans and mammalian infection results in endothelial cell barrier dysfunction and increased vascular permeability. We previously demonstrated that treatment of Rickettsia parkeri-infected cells with the calcium channel blocker benidipine significantly delayed vascular barrier permeability. Thus, we hypothesized that benidipine, known to be safe and effective for other clinical processes, could reduce rickettsia-induced vascular permeability in vivo in an animal model of spotted fever rickettsiosis. Based on liver, lung and brain vascular FITC-dextran extravasation studies, benidipine did not reliably impact vascular permeability. However, it precipitated a deleterious effect on responses to control sublethal R. parkeri infection. Animals treated with benidipine alone had no clinical signs or changes in histopathology and splenic immune cell distributions. Benidipine-treated infected animals had marked increases in tissue and blood bacterial loads, more extensive inflammatory histopathologic injury, and changes in splenic architecture and immune cell distributions potentially reflecting diminished Ca2+ signaling, reduced innate immune cell activation, and loss of rickettsial propagation control. Impaired T cell activation by R. parkeri antigen in the presence of benidipine was confirmed in vitro with the use of NKT cell hybridomas. The unexpected findings stand in stark contrast to recent discussions of the benefits of calcium channel blockers for viral infections and chronic infectious or inflammatory diseases. A role for calcium channel blockers in exacerbation of human rickettsiosis and acute inflammatory infections should be evaluated by a retrospective review of patient's outcomes and medications.

Reduced Monocyte and Neutrophil Infiltration and Activation by P-Selectin/CD62P Inhibition Enhances Thrombus Resolution in Mice.

Venous thromboembolism is a major health problem. After thrombus formation, its resolution is essential to re-establish blood flow, which is crucially mediated by infiltrating neutrophils and monocytes in concert with activated platelets and endothelial cells. Thus, we aimed to modulate leukocyte function during thrombus resolution post-thrombus formation by blocking P-selectin/CD62P-mediated cell interactions. Thrombosis was induced by inferior vena cava stenosis through ligation in mice. After 1 day, a P-selectin-blocking antibody or isotype control was administered and thrombus composition and resolution were analyzed. Localizing neutrophils and macrophages in thrombotic lesions of wild-type mice revealed that these cells enter the thrombus and vessel wall from the caudal end. Neutrophils were predominantly present 1 day and monocytes/macrophages 3 days after vessel ligation. Blocking P-selectin reduced circulating platelet-neutrophil and platelet-Ly6Chigh monocyte aggregates near the thrombus, and diminished neutrophils and Ly6Chigh macrophages in the cranial thrombus part compared with isotype-treated controls. Depletion of neutrophils 1 day after thrombus initiation did not phenocopy P-selectin inhibition but led to larger thrombi compared with untreated controls. In vitro, P-selectin enhanced human leukocyte function as P-selectin-coated beads increased reactive oxygen species production by neutrophils and tissue factor expression of classical monocytes. Accordingly, P-selectin inhibition reduced oxidative burst in the thrombus and tissue factor expression in the adjacent vessel wall. Moreover, blocking P-selectin reduced thrombus density determined by scanning electron microscopy and increased urokinase-type plasminogen activator levels in the thrombus, which accelerated caudal fibrin degradation from day 3 to day 14. This accelerated thrombus resolution as thrombus volume declined more rapidly after blocking P-selectin. Inhibition of P-selectin-dependent activation of monocytes and neutrophils accelerates venous thrombosis resolution due to reduced infiltration and activation of innate immune cells at the site of thrombus formation, which prevents early thrombus stabilization and facilitates fibrinolysis.

Advances in lung ischemia/reperfusion injury: unraveling the role of innate immunity.

Lung ischemia/reperfusion injury (LIRI) is a common occurrence in clinical practice and represents a significant complication following pulmonary transplantation and various diseases. At the core of pulmonary ischemia/reperfusion injury lies sterile inflammation, where the innate immune response plays a pivotal role. This review aims to investigate recent advancements in comprehending the role of innate immunity in LIRI. A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning lung ischemia/reperfusion injury, cell death, damage-associated molecular pattern molecules (DAMPs), innate immune cells, innate immunity, inflammation. During the process of lung ischemia/reperfusion, cellular injury even death can occur. When cells are injured or undergo cell death, endogenous ligands known as DAMPs are released. These molecules can be recognized and bound by pattern recognition receptors (PRRs), leading to the recruitment and activation of innate immune cells. Subsequently, a cascade of inflammatory responses is triggered, ultimately exacerbating pulmonary injury. These steps are complex and interrelated rather than being in a linear relationship. In recent years, significant progress has been made in understanding the immunological mechanisms of LIRI, involving novel types of cell death, the ability of receptors other than PRRs to recognize DAMPs, and a more detailed mechanism of action of innate immune cells in ischemia/reperfusion injury (IRI), laying the groundwork for the development of novel diagnostic and therapeutic approaches. Various immune components of the innate immune system play critical roles in lung injury after ischemia/reperfusion. Preventing cell death and the release of DAMPs, interrupting DAMPs receptor interactions, disrupting intracellular inflammatory signaling pathways, and minimizing immune cell recruitment are essential for lung protection in LIRI.

Lipid peroxidation of immune cells in cancer.

Growing evidence indicates that cellular metabolism is a critical determinant of immune cell viability and function in antitumor immunity and lipid metabolism is important for immune cell activation and adaptation to the tumor microenvironment (TME). Lipid peroxidation is a process in which oxidants attack lipid-containing carbon-carbon double bonds and is an important part of lipid metabolism. In the past decades, studies have shown that lipid peroxidation participates in signal transduction to control cell proliferation, differentiation, and cell death, which is essential for cell function execution and human health. More importantly, recent studies have shown that lipid peroxidation affects immune cell function to modulate tumor immunity and antitumor ability. In this review, we briefly overview the effect of lipid peroxidation on the adaptive and innate immune cell activation and function in TME and discuss the effectiveness and sensitivity of the antitumor ability of immune cells by regulating lipid peroxidation.

The ins and outs of lipoprotein(a) assay methods.

Pathophysiological, epidemiological and genetic studies convincingly showed lipoprotein(a) (Lp(a)) to be a causal mediator of atherosclerotic cardiovascular disease (ASCVD). This happens through a myriad of mechanisms including activation of innate immune cells, endothelial cells as well as platelets. Although these certainties whether or not Lp(a) is ready for prime-time clinical use remain debated. Thus, remit of the present review is to provide an overview of different methods that have been employed for the measurement of Lp(a). The methods include dynamic light scattering, multi-angle light scattering analysis, near-field imaging, sedimentation, gel filtration, and electron microscopy. The development of multiple Lp(a) detection methods is vital for improved prediction of ASCVD risk.

Innate immune responses to SARS-CoV-2.

This chapter provides an overview of the innate immune response to SARS-CoV-2, focusing on the recognition, activation, and evasion strategies employed by the virus. The innate immune system plays a crucial role in the early defense against viral infections, and understanding its response to SARS-CoV-2 is essential for developing effective therapeutic approaches. The chapter begins by explaining the basics of the innate immune system, including its components and salient features. It discusses the various pattern recognition receptors involved in recognizing SARS-CoV-2, such as toll-like receptors, RIG-I-like receptors, NOD-like receptors, and other cytosolic sensors. The binding and entry of the virus into host cells and subsequent activation of innate immune cells, including neutrophils, monocytes, macrophages, dendritic cells, NK cells, and ILCs, are explored. Furthermore, the secretion of key cytokines and chemokines, including type I interferons, IL-6, IL-17, and TNF-alpha, is discussed as part of the innate immune response. The concept of PANoptosis, involving programmed cell death mechanisms, is introduced as a significant aspect of the response to SARS-CoV-2. The chapter also addresses the innate immune evasion strategies employed by SARS-CoV-2, which allow the virus to evade or subvert the host immune response, contributing to viral persistence. Understanding these strategies is crucial for developing targeted therapies against the virus.

Biocompatible metal-organic frameworks as promising platforms to eradicate HIV reservoirs ex vivo in people living with HIV.

The HIV attacks the immune system provoking an infection that is considered a global health challenge. Despite antiretroviral treatments being effective in reducing the plasma viral load in the blood to undetectable levels in people living with HIV (PLWH), the disease is not cured and has become chronic. This happens because of the existence of anatomical and cellular viral reservoirs, mainly located in the lymph nodes and gastrointestinal tract, which are composed of infected CD4+ T cells with a resting memory phenotype and inaccessible to antiretroviral therapy. Herein, a new therapeutic strategy based on nanotechnology is presented. Different combinations of antiretroviral drugs (bictegravir/tenofovir/emtricitabine and nevirapine/tenofovir/emtricitabine) and toll-like receptor agonists were encapsulated into metal-organic frameworks (MOFs) PCN-224 and ZIF-8. The encapsulation efficiencies of all the drugs, as well as their release rate from the carriers, were measured. In vitro studies about the cell viability, the hemocompatibility, and the platelet aggregation of the MOFs were carried out. Epifluorescence microscopy assays confirmed the ability of ZIF-8 to target a carboxyfluorescein probe inside HeLa cell lines and PBMCs. These results pave the way for the use of these structures to eliminate latent HIV reservoirs from anatomical compartments through the activation of innate immune cells, and a higher efficacy of the triplet combinations of antiretroviral drugs.

Based on Weighted Gene Co-Expression Network Analysis Reveals the Hub Immune Infiltration-Related Genes Associated with Ulcerative Colitis.

Immune infiltration plays a pivotal role in the pathogenesis of mucosal damage in ulcerative colitis (UC). The objective of this study was to systematically analyze and identify genetic characteristics associated with immune infiltration in UC. Gene expression data from three independent datasets obtained from the Gene Expression Omnibus (GEO) were utilized. By employing the ssGSEA and CIBERSORT algorithms, we estimated the extent of immune cell infiltration in UC samples. Subsequently, Weighted Correlation Network Analysis (WGCNA) was performed to identify gene modules exhibiting significant associations with immune infiltration, and further identification of hub genes associated with immune infiltration was accomplished using least absolute shrinkage and selection operator (LASSO) regression analysis. The relationship between the identified hub genes and clinical information was subsequently investigated. Our findings revealed significant activation of both innate and adaptive immune cells in UC. Notably, the expression levels of CD44, IL1B, LYN, and ITGA5 displayed strong correlations with immune cell infiltration within the mucosa of UC patients. Immunohistochemical analysis confirmed the significant upregulation of CD44, LYN, and ITGA5 in UC samples, and their expression levels were found to be significantly associated with common inflammatory markers, including the systemic immune inflammation indices, C-reactive protein, and erythrocyte sedimentation rate. CD44, LYN, and ITGA5 are involved in the immune infiltration pathogenesis of UC and may be potential therapeutic targets for UC.