Type Of Inflammatory Response Research Articles

The effect of N-eicosapentaenoyl ethanolamine on the regulation of cytokine synthesis by blood cells of patients with bronchial asthma <I>in vitro</I>

Introduction. Bronchial asthma is characterized by heterogeneity, multiple phenotypes, and varying clinical manifestations. Cytokines play a crucial role in the inflammatory response in asthma. The quantity, as well as the ratio of certain cytokines, determines the mechanism and type of inflammatory response in asthma, upon which the effectiveness of treatment of this disease depends. That is why the development of new methods of treating patients with asthma, aimed at correcting cytokine imbalance, is required. One of the promising substances is N-eicosapentaenoyl-ethanolamine (NAE-EPA), which exhibits anti-inflammatory properties by affecting cytokines, but remains poorly studied.Aim. To study the dose-dependent effect of N-eicosapentaenoyl-ethanolamine on the production of cytokines by peripheral blood cells, in vitro, in subjects with asthma.Materials and methods. The object of the study was whole blood, diluted 1:5 with culture medium of 15 patients with mild to moderate controlled asthma and 16 healthy subjects. The in vitro experiment was carried out in lipopolysaccharide-stimulated (LPS) blood samples (incubation with LPS at 37°C for 30 minutes). Then, the experimental substance N-acylethanolamine eicosapentaenoic acid (NAE EPA) was added in concentrations of 1.0; 5.0, and 10.0 µM and incubated at 37°C for 6 hours with gentle mixing. Cytokine levels (IL-2, IL-4, IL-6, IL-10, IL17A, TNF-α, and INF-γ) were studied by enzyme-linked immunoassay.Results. Analysis of the level of cytokines in patients with asthma showed that an increase in the plasma levels of IL-2, TNF-α, IL-6, and IL-17A is accompanied by a decrease in the level of regulatory IL-10. When NAE EPA was added at a dosage of 1 µM, no statistically significant changes were detected. Exposure to the experimental substance at a dose of 5 µM contributed to a decrease in IL-6 in the blood cells of patients by 19% (p ˂ 0.05). Exposure to NAE EPA at 10 µM produced the greatest number of statistically significant changes in cytokine levels. There was a decrease in IL-17A by 15% (p ˂ 0.05), IL-2 by 14% (p ˂ 0.05), IL-6 by 50% (p ˂ 0.01), and TNF-α by 10% (p ˂ 0.05) relative to values before exposure.Conclusion. N-eicosapentaenoyl ethanolamine shows potential as a regulator of pro- and anti-inflammatory cytokine synthesis in bronchial asthma with a predominant Th-17 type of immune response. The results obtained may contribute to the development of new treatment strategies for patients with asthma.

Genetic and gut microbiome determinants of SCFA circulating and fecal levels, postprandial responses and links to chronic and acute inflammation

ABSTRACT Short-chain fatty acids (SCFA) are involved in immune system and inflammatory responses. We comprehensively assessed the host genetic and gut microbial contribution to a panel of eight serum and stool SCFAs in two cohorts (TwinsUK, n = 2507; ZOE PREDICT-1, n = 328), examined their postprandial changes and explored their links with chronic and acute inflammatory responses in healthy individuals and trauma patients. We report low concordance between circulating and fecal SCFAs, significant postprandial changes in most circulating SCFAs, and a heritable genetic component (average h2 : serum = 14%(SD = 14%); stool = 12%(SD = 6%)). Furthermore, we find that gut microbiome can accurately predict their fecal levels (AUC>0.71) while presenting weaker associations with serum. Finally, we report different correlation patterns with inflammatory markers depending on the type of inflammatory response (chronic or acute trauma). Our results illustrate the breadth of the physiological relevance of SCFAs on human inflammatory and metabolic responses highlighting the need for a deeper understanding of this important class of molecules.

Biocompatible Short-Peptides Fibrin Co-assembled Hydrogels.

Fibrin hydrogels made by self-assembly of fibrinogen obtained from human plasma have shown excellent biocompatible and biodegradable properties and are widely used in regenerative medicine. The fibrinogen self-assembly process can be triggered under physiological conditions by the action of thrombin, allowing the injection of pregel mixtures that have been used as cell carriers, wound-healing systems, and bio-adhesives. However, access to fibrinogen from human plasma is expensive and fibrin gels have limited mechanical properties, which make them unsuitable for certain applications. One solution to these problems is to obtain composite gels made of fibrin and other polymeric compounds that improve their mechanical properties and usage. Herein, we prepared composite hydrogels made by the self-assembly of fibrinogen together with Fmoc-FF (Fmoc-diphenylalanine) and Fmoc-RGD (Fmoc-arginine-glycine-aspartic acid). We have shown that the mixture of these three peptides co-assembles and gives rise to a unique type of supramolecular fiber, whose morphology and mechanical properties can be modulated. We have carried out a complete characterization of these materials from chemical, physical, and biological points of view. Composite gels have improved mechanical properties compared to pure fibrin gels, as well as showing excellent biocompatibility ex vivo. In vivo experiments have shown that these gels do not cause any type of inflammatory response or tissue damage and are completely resorbed in short time, which would enable their use as vehicles for cell, drug, or growth factor release.

Alveolar macrophages and airway hyperresponsiveness associated with respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is a ubiquitous pathogen of viral bronchiolitis and pneumonia in children younger than 2 years of age, which is closely associated with recurrent wheezing and airway hyperresponsiveness (AHR). Alveolar macrophages (AMs) located on the surface of the alveoli cavity are the important innate immune barrier in the respiratory tract. AMs are recognized as recruited airspace macrophages (RecAMs) and resident airspace macrophages (RAMs) based on their origins and roaming traits. AMs are polarized in the case of RSV infection, forming two macrophage phenotypes termed as M1-like and M2-like macrophages. Both M1 macrophages and M2 macrophages are involved in the modulation of inflammatory responses, among which M1 macrophages are capable of pro-inflammatory responses and M2 macrophages are capable of anti-proinflammatory responses and repair damaged tissues in the acute and convalescent phases of RSV infection. Polarized AMs affect disease progression through the alteration of immune cell surface phenotypes as well as participate in the regulation of T lymphocyte differentiation and the type of inflammatory response, which are closely associated with long-term AHR. In recent years, some progress have been made in the regulatory mechanism of AM polarization caused by RSV infection, which participates in acute respiratory inflammatory response and mediating AHR in infants. Here we summarized the role of RSV-infection-mediated AM polarization associated with AHR in infants.

Characterization of chronic relapsing antibody mediated arthritis in mice with a mutation in Ncf1 causing reduced oxidative burst

Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting joints with a hallmark of autoantibody production. Mannan-enhanced collagen type II (COL2) antibody induced arthritis (mCAIA) in neutrophil cytosolic factor 1(Ncf1) mutation mouse is a chronic disease model imitating RA in mice. In this study, we characterize the chronic phase of mCAIA in Ncf1 mutated (BQ.Ncf1m1j/m1j) mice. Arthritis was induced by an intravenous injection of anti-COL2 monoclonal antibodies on day 0 followed by intra-peritoneal injections of mannan (from Saccharomyces cerevisiae) on days 3 and 65 in BQ.Ncf1m1j/m1j and BQ mice. Bone erosion was analysed by computed tomography (CT) and blood cell phenotypes by flow cytometry. Cytokines and anti-COL2 antibodies were analyzed with multiplex bead-based assays. The arthritis in the Ncf1m1j/m1j mice developed with a chronic and relapsing disease course, which was followed for 200 days and bone erosions of articular joints were evaluated. An increased number of circulating CD11b+ Ly6G+ neutrophils were observed during the chronic phase, together with a higher level of G-CSF (granulocyte colony-stimulating factor) and TNF-α. In conclusion, the chronic relapsing arthritis of mCAIA in the Ncf1m1j/m1j mice develop bone erosions associated with a sustained neutrophil type of inflammatory responses.

The efficacy and safety of immunobiological therapy of atopic dermatitis in children

The review shows atopic dermatitis (AD) as a chronic inflammatory skin disease that develops in early childhood in infants with a hereditary predisposition. The inflammatory response type 2, including a complex interaction of type 2 T-helpers (Th2), congenital lymphoid cells, granulocytes (including eosinophils, mast cells and basophils), cytokines (IL-4, IL-5, IL-13 etc.) and immunoglobulin E (IgE) underlie at the base of the AD pathogenesis. IL-4 and IL-13 deserve special attention since they affect several links of pathogenesis at once. Both cytokines interact with receptors. Their critical subunit is the alpha chain of the IL-4 receptor. This molecule is the target for dupilumab, the first genetically engineered biologically active drug that demonstrated the high efficacy in the treatment of AD in 6 to 18-year children patients. At the same time, the data available in the literature indicates the drug to have both nonspecific (soreness at the injection site, allergic response) and specific (conjunctivitis, secondary herpetic infections, eosinophilia) adverse effects, which should be taken into account by practitioners when prescribing immunobiological therapy. Conclusion. In randomised, double-blind, placebo-controlled trials in children of different ages with the moderate to severe course of AD, immunobiological therapy with dupilumab has demonstrated high clinical efficacy in the form of a rapid remission of the disease and exemplary safety.

Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity.

The immunosuppressive function of regulatory T (Treg) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss-of-function or induced ablation of Treg cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from Treg cell paucity, highlighting a vital function of Treg cells in preventing fatal autoimmune inflammation. However, a major question remains whether Treg cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate Treg cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of “redeemed” Treg cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease, and provided long-term protection against them. Thus, Treg cells are functional in settings of established broad spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.

Dynamic of Cytokine Storm in Human Inflammatory Response of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-Induced Disease

Infection of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in the human body is characterized by the detection of large amounts of the virus by cytokine as the response to inflammation. In the human body, there are two types of inflammatory responses by a cytokine called pro-inflammatory and anti-inflammatory cytokine. A non-dimensionalized mathematical model of the inflammatory response system has been constructed in the form of a system of differential equations, which consists of two variables and five parameters. The rate of pro-inflammatory and anti-inflammatory cytokine natural production are two important parameters that correlate with a chronic SARS-CoV infection called a cytokine storm. Varying these parameter values, some non-chaotic torus attractors were found in some numerical simulation with the initial value around the equilibrium point obtained by fixing parameter values at the Generalized Hopf bifurcation point. These phenomena show that in cytokine storm condition, fluctuation of pro-inflammatory and anti-inflammatory cytokines form some patterns which are complex, so that they are difficult to be predicted. Mesenchymal stem cells (MSC), chloroquine (CQ), and hydroxychloroquine (HCQ), which have an effect on pro-inflammatory and anti-inflammatory cytokine production, can be used to reduce the cytokine storm.

Molecular mechanism of asthma and its novel molecular target therapeutic agent.

Asthma is a chronic disease with major public health ramifications owing to its high morbidity and mortality rates, especially in severe and recurrent cases. Conventional therapeutic options could partially alleviate the burden of asthma, yet a novel approach is needed to completely control this condition. To do so, a comprehensive understanding of the molecular mechanism underlying asthma is essential to recognize and treat the major pathways that drive its pathophysiology. In this review, we will discuss the molecular mechanism of asthma, in particular focusing on the type of inflammatory responses it elicits, namely type 2 and non-type 2 asthma. Furthermore, we will discuss the novel therapeutic options that target the aberrant molecules found in asthma pathophysiology. We will specifically focus on the role of novel monoclonal antibody therapies recently developed, such as the anti-IgE, IL-5, IL-5Rα, and IL-4Rα antibodies, drugs that have been extensively studied preclinically and clinically.

Diseases and parasites of wild and cultivated mussels along the Patagonian coast of Argentina, southwest Atlantic Ocean.

A histological survey of the commercially edible mussels Mytilus platensis and M. chilensis from wild and cultivated populations along the coast of Patagonia, Argentina (42°00' to 54°47'S), was carried out to determine their health status. Diagnostic results included 3 types of inflammatory responses (infiltrative, nodular, and encapsulation), disseminated neoplasia disease, 2 abnormal reproductive conditions (gonadal atresia and intersex), prokaryotic inclusions, protozoans, and metazoans. Pathogen prevalence and infection intensity among mussels of different sampling sites and between those of wild and cultivated populations were compared. Inflammatory responses were recorded in all mussels from all sites, while disseminated neoplasia only occurred in the most southern cultivated M. chilensis. Intracellular prokaryotic inclusions were broadly distributed in the mussels from both northern and southern Patagonian coasts. Ciliates showed the highest prevalence among wild mussels from the colder waters of Bahía Brown. Turbellaria were recorded at higher prevalence in cultured mussels (41.7%), and trematode metacercariae occurred exclusively in intertidal wild mussels. None of the parasites found appears to be a problem to the fishery or farming, although disseminated neoplasia should be monitored. In addition, we found that mytilid species coexisting with M. platensis (Aulacomya atra and Perumytilus purpuratus) at one location shared the same pathological conditions and parasites, which differed from those of M. platensis at a distant locality. These results suggest that pathological conditions and parasites were influenced more by ecological habitat factors than by the species of mussels present, based on similar parasite assemblages found among closely related mytilid hosts in the same geographical area.

Coronavirus SARS-CoV-2: filtering fact from fiction in the infodemic: Q&A with virologist Professor Urs Greber.

Coronavirus SARS-CoV-2: filtering fact from fiction in the infodemic: Q&A with virologist Professor Urs Greber.

Multiparameter Analysis Identifies Heterogeneity in Knee Osteoarthritis Synovial Responses.

Synovial membrane inflammation is common in osteoarthritis (OA) and increases cartilage injury. However, synovial fluid and histology studies suggest that OA inflammatory responses are not homogeneous. Greater understanding of these responses may provide new insights into OA disease mechanisms. We undertook this study to develop a novel multiparameter approach to phenotype synovial responses in knee OA. Cell composition and soluble protein production were measured by flow cytometry and multiplex enzyme-linked immunosorbent assay in synovium collected from OA patients undergoing knee replacement surgery (n = 35). Testing disaggregation conditions showed that aggressive digestion improved synovial cell yield and mesenchymal staining by flow cytometry, but it negatively impacted CD4+ T cell and CD56+ natural killer cell staining. Less aggressive digestion preserved these markers and showed highly variable T cell infiltration (range 0-43%; n = 32). Correlation analysis identified mesenchymal subpopulations associated with different nonmesenchymal populations, including macrophages and T cells (CD45+CD11b+HLA-DR+ myeloid cells with PDPN+CD73+CD90-CD34- mesenchymal cells [r = 0.65, P < 0.0001]; and CD45+CD3+ T cells with PDPN+CD73+CD90+CD34+ mesenchymal cells [r = 0.50, P = 0.003]). Interleukin-6 (IL-6) measured by flow cytometry strongly correlated with IL-6 released by ex vivo culture of synovial tissue (r = 0.59, P = 0.0012) and was highest in mesenchymal cells coexpressing CD90 and CD34. IL-6, IL-8, complement factor D, and IL-10 release correlated positively with tissue cellularity (P = 0.0042, P = 0.018, P = 0.0012, and P = 0.038, respectively). Additionally, increased CD8+ T cell numbers correlated with retinol binding protein 4 (P = 0.033). Finally, combining flow cytometry and multiplex data identified patient clusters with different types of inflammatory responses. We used a novel approach to analyze OA synovium, identifying patient-specific inflammatory clusters. Our findings indicate that phenotyping synovial inflammation may provide new insights into OA patient heterogeneity and biomarker development.

Immunohistochemical evaluation of CD117 in mast cell of aggressive periodontitis.

Context:Aggressive periodontitis is a type of inflammatory response in periodontal tissues that is differentiated from chronic by its earlier onset, its high rate of progression, subgingival microbial composition, the difference in the host's immune response, and family history of the disease. Mast cells live in tissues and contribute to the various allergic and inflammatory conditions, including periodontal diseases, through the release of cytokines, chemokines, and proteolytic enzymes. CD117, the receptor of the stem cell factor expressed by the mast cells, is the hallmark of mast cell development. This study aimed to determine the expression level of CD117 in the mast cells of aggressive periodontitis using immunohistochemistry.Aims:This study aimed to determine the expression level of CD117 in the mast cells of aggressive periodontitis using immunohistochemistry.Subjects and Methods:The study was conducted on tissue samples from 15 patients with aggressive periodontitis and 15 patients with healthy gingival tissue. Samples were stained for CD117 markers using immunohistochemistry. After the microscopic examination of samples, all data were entered into SPSS 20 and analyzed.Statistical Analysis Used:Statistical data were analyzed using Kolmogorov–Smirnov test and independent t-test.Results:According to the results, the mean expression levels of CD117 in the aggressive periodontitis and normal gingival groups were 19.08 ± 6.9 and 18.2 ± 8.1, respectively, which were not statistically significant (P = 0.75). The Kolmogorov–Smirnov test verified the normality of distribution of CD117 expression level. Given the normal distribution of the scores, the independent t-test was used to compare the CD117 expression level in the two study groups.Conclusions:There was no significant difference in the level of CD117 expression between the control and aggressive periodontitis groups.

Histopathological features of subcutaneous mycosis: a retrospective study

Background: Subcutaneous fungal infection is commonly seen in tropical and subtropical countries particularly in India. The lesions are usually presented as swelling, in the localized form. Subcutaneous mycosis is caused by penetration of causative fungi into the subcutaneous tissue. Histopathology is one of the main tools of diagnosis in mycology as it has the advantages of early diagnosis compared to culture, low cost and it provides a presumptive identification of the infecting fungus. It also gives information about tissue reaction and supplement culture report. It gives the idea about the fungus isolated in culture is contaminant or pathogenic. Many a times tissue might be sent in formalin as fungal infection is not suspected clinically. Role of histopathologist is very important in diagnosing these subcutaneous fungal lesions. Material &amp;Methods: A retrospective study was conducted on subcutaneous fungal infections seen between January 2014 to December 2018 in the Department of pathology, IGMC&amp;RI, Puducherry. Twenty-two patients with biopsy proven subcutaneous fungal infections were included in the study. In the present study, the varied histopathological features like type of inflammatory response, presence of granulomas, necrosis, eosinophils and abscess formation were seen in the tissue sections. Results: The most common histopathology feature was giant cell reaction seen in 21 (95.5%) cases, followed by epithelioid cell granuloma in 13(59%) cases and areas of necrosis in 13 (59%) cases. Eight (36%) cases showed numerous eosinophilic infiltration 10(46%) cases of scant eosinophils and 4 (18%) cases showed absent eosinophils. These fungal structures were identified in H&amp;E stain itself in 13 (59%) cases. Conclusion: Histopathological study is most important in subcutaneous mycosis as most of the time diagnosis is unsuspected and delayed because of its rarity and varied presentation. Fungal infection should be suspected in cases with localized cystic swelling. High index of suspicion, careful microscopic examination and special stains are important for accurate diagnosis.

Have Outbreaks of the World Health Organisation’s Disease X Been Identified?

The World Health Organisation (WHO) has recently highlighted the possibility of a curious Disease X with potential to cause an international public health emergency. This research update details the progress to-date at identifying potential outbreaks of Disease X. During these outbreaks’ medical admissions and deaths, but not surgical, increase for an approximate 12-month duration, before reverting to the baseline level. These outbreaks appear to initiate most commonly in the interval from the end of winter to the end of spring. A range of medical admissions increase which seemingly have a common immune function linkage, possibly related to certain types of inflammatory response. Research on alternative immune steady states presents a possible basis for this on/off switching of population health. As the WHO have noted, urgent research is required to further document these alarming disease outbreaks, which have eluded traditional disease surveillance methodologies.

Immune Mediator Profile in Aqueous Humor Differs in Patients with Primary Acquired Ocular Toxoplasmosis and Recurrent Acute Ocular Toxoplasmosis

Purpose To compare the intraocular cytokine and chemokine profiles in patients with acute primary acquired ocular toxoplasmosis (pOT) or recurrent ocular toxoplasmosis (rOT) and to correlate them with their clinical characteristics. Methods Aqueous humor samples were collected from 62 consecutive patients (21 pOT, 30 rOT, and 11 noninfected controls) and analyzed by multiplex assay. Correlations were assessed between cytokine/chemokine levels, type of inflammatory response (Th1, Th2, and Th17), and clinical characteristics. In all OT patients, the clinical diagnosis of either pOT or rOT was confirmed by positive intraocular Goldmann/Witmer-Desmonts coefficient. Correlations were assessed between a preselected panel of immune mediators and the clinical characteristics of OT. Results In pOT patients, increased levels of IL-2, IFN-γ, TNF-α, IL-15, IL-4, IL-5, IL-9, IL-13, IL-17, IL-1Rα, IL-6, IL-1β, and chemokines MIP-1α, MIP-1β, IP-10, Eotaxin, IL-8, RANTES, PDGF-bb, GM-CSF, G-CSF, and MCP-1 were found in comparison to those in controls (p < 0.05). Patients with rOT showed elevated levels of IL-2, IFN-γ, TNF-α, IL-15, IL-4, IL-5, IL-9, IL-17, IL-1Rα, IL-6, IL-1β, and chemokines MIP-1α, IP-10, Eotaxin, IL-8, RANTES, PDGF-bb, G-CSF, and MCP-1 compared to controls (p < 0.05). In addition, IL-7 (p = 0.028) differed between pOT and rOT; IL-9 (p = 0.054) and IL-13 (p = 0.051) showed a tendency of higher concentration in pOT than in rOT. A negative correlation was found between IL-7 (p = 0.017) as well as IL-9 (p = 0.008) and the number of recurrences. Cytokine ratios showed no difference between pOT and rOT, indicating a dominant Th1-type response in both infectious groups. Moreover, a positive correlation was detected between IL-7, VEGF, IL-13 and age at aqueous humor sampling (p < 0.05). Conclusions This study for the first time shows subtle differences between the intraocular cytokine profiles in patients with either acute pOT or rOT.

Immunobiology of Inherited Muscular Dystrophies.

The immune response to acute muscle damage is important for normal repair. However, in chronic diseases such as many muscular dystrophies, the immune response can amplify pathology and play a major role in determining disease severity. Muscular dystrophies are inheritable diseases that vary tremendously in severity, but share the progressive loss of muscle mass and function that can be debilitating and lethal. Mutations in diverse genes cause muscular dystrophy, including genes that encode proteins that maintain membrane strength, participate in membrane repair, or are components of the extracellular matrix or the nuclear envelope. In this article, we explore the hypothesis that an important feature of many muscular dystrophies is an immune response adapted to acute, infrequent muscle damage that is misapplied in the context of chronic injury. We discuss the involvement of the immune system in the most common muscular dystrophy, Duchenne muscular dystrophy, and show that the immune system influences muscle death and fibrosis as disease progresses. We then present information on immune cell function in other muscular dystrophies and show that for many muscular dystrophies, release of cytosolic proteins into the extracellular space may provide an initial signal, leading to an immune response that is typically dominated by macrophages, neutrophils, helper T-lymphocytes, and cytotoxic T-lymphocytes. Although those features are similar in many muscular dystrophies, each muscular dystrophy shows distinguishing features in the magnitude and type of inflammatory response. These differences indicate that there are disease-specific immunomodulatory molecules that determine response to muscle cell damage caused by diverse genetic mutations. © 2018 American Physiological Society. Compr Physiol 8:1313-1356, 2018.

Abstract P4-03-09: Human breast cancer biopsies induce eosinophil recruitment and enhance adjacent cancer cell proliferation

Abstract Previous research has demonstrated that chronic inflammation facilitates cancer progression and spread to other sites. The effect of acute inflammation in the microenvironment of the tumor that develops as a result of standard biopsy procedures has not been studied in detail. Recent studies demonstrated that acute inflammation in mouse models from a mammary biopsy increases the frequency of distal cancer metastasis. Core needle biopsies are the standard procedure for breast cancer diagnosis, but there have been no studies detailing the inflammatory response from the biopsy. The purpose of this study is to determine if core needle biopsies in breast cancer patients trigger an inflammatory response, determine the type of inflammatory response that occurs and study the potential effect of acute inflammatory response on tumor cells remaining. The biopsy wound site was identified in primary tumor resection samples from breast cancer patients. The inflammatory response adjacent and distant to the biopsy were studied via histology and immunohistochemistry. Tumor cell proliferation was studied as well. Our study demonstrated that diagnostic core needle biopsies trigger inflammatory cell recruitment at the site, and those cells remain over long periods of time. An unexpected increase in eosinophils were found to accumulate at the biopsy site. The biopsy also was shown to increase proliferation adjacent to the wound site. Overall, core needle biopsies used for breast cancer diagnosis induce a unique inflammatory environment at the site of the biopsy as well as the closely surrounding cells. Inflammation induced by the biopsy could lead to tumor cell progression or metastasis in breast cancer. These findings may be important for the clinical management of breast cancer. Citation Format: Spencer BL, Szalayova G, Ogodnik A, Rincon M, James T. Human breast cancer biopsies induce eosinophil recruitment and enhance adjacent cancer cell proliferation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-03-09.

Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer

Regulatory T (Treg) cells reside in lymphoid organs and barrier tissues where they control different types of inflammatory responses. Treg cells are also found in human cancers, and studies in animal models suggest that they contribute to cancer progression. However, properties of human intratumoral Treg cells and those present in corresponding normal tissue remain largely unknown. Here, we analyzed features of Treg cells in untreated human breast carcinomas, normal mammary gland, and peripheral blood. Tumor-resident Treg cells were potently suppressive and their gene-expression pattern resembled that of normal breast tissue, but not of activated peripheral blood Treg cells. Nevertheless, a number of cytokine and chemokine receptor genes, most notably CCR8, were upregulated in tumor-resident Treg cells in comparison to normal tissue-resident ones. Our studies suggest that targeting CCR8 forthe depletion of tumor-resident Treg cells might represent a promising immunotherapeutic approach for the treatment of breast cancer.

Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression during Endoplasmic Reticulum Stress

Perturbation of endoplasmic reticulum (ER) homeostasis triggers the ER stress response (also known as Unfolded Protein Response), a hallmark of many pathological disorders. However the connection between ER stress and inflammation remains largely unexplored. Recent data suggest that ER stress controls the activity of inflammasomes, key signaling platforms that mediate innate immune responses. Here we report that expression of NLRP1, a core inflammasome component, is specifically up-regulated during severe ER stress conditions in human cell lines. Both IRE1α and PERK, but not the ATF6 pathway, modulate NLRP1 gene expression. Furthermore, using mutagenesis, chromatin immunoprecipitation and CRISPR-Cas9-mediated genome editing technology, we demonstrate that ATF4 transcription factor directly binds to NLRP1 promoter during ER stress. Although involved in different types of inflammatory responses, XBP-1 splicing was not required for NLRP1 induction. This study provides further evidence that links ER stress with innate