This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Early Growth Response Genes (EGR) is a family of four transcription factors containing a unique zinc finger domain. EGR-2 and EGR-3 are important for hindbrain development and myelination. These transcription factors are also necessary for lymphocyte function however, the mechanisms are still unclear. Previous findings have shown that EGR-2cKO mice develop lupus-like autoimmune disease with high levels of pro-inflammatory cytokines despite showing normal T and B cell proliferation after mitogenic stimulation. Therefore we established the CD2-EGR-2-/-EGR-3-/- mouse model to explore the phenotype, susceptibility to autoimmune disease and relevant lymphocyte function. We discovered that CD2-EGR-2-/-EGR-3-/- mice developed severe systemic autoimmune disease and expressed high levels of inflammatory cytokines. More importantly we discovered a novel finding that CD2-EGR-2-/-EGR-3-/- T and B cells had impaired cell proliferation after mitogenic stimulation. Further investigations revealed that the molecular mechanism defected in the T cell receptor signalling pathway is due to a dysfunction in Activator Protein-1 (AP-1). AP-1 is a heterodimeric protein composed of AP-1 family members including Jun, Atf and Fos. Our data shows that EGR-2 and EGR-3 directly bind with the Atf family member Batf, which prevents Batf’s inhibitory function on AP-1 activation. This research demonstrates that EGR-2 and EGR-3 intrinsically regulate chronic inflammation and also positively regulate antigen receptor activation. In conclusion EGR-2 and EGR-3 are essential for providing optimal immune responses, whilst limiting inflammatory immunopathology. We propose that this new model could be used for studying autoimmune disease

The immune response is essential to protect organisms from infection and an altered self. An organism’s overall metabolic status is now recognized as an important and long-overlooked mediator of immunity and has spurred new explorations of immune-related metabolic abnormalities. Peroxisomes are essential metabolic organelles with a central role in the synthesis and turnover of complex lipids and reactive species. Peroxisomes have recently been identified as pivotal regulators of immune functions and inflammation in the development and during infection, defining a new branch of immunometabolism. This review summarizes the current evidence that has helped to identify peroxisomes as central regulators of immunity and highlights the peroxisomal proteins and metabolites that have acquired relevance in human pathologies for their link to the development of inflammation, neuropathies, aging and cancer. This review then describes how peroxisomes govern immune signaling strategies such as phagocytosis and cytokine production and their relevance in fighting bacterial and viral infections. The mechanisms by which peroxisomes either control the activation of the immune response or trigger cellular metabolic changes that activate and resolve immune responses are also described.

Yan Wang,1,2 Junshun Chang,1 Ben Hu,3 Suyun Yang1 1Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, People’s Republic of China; 2Academy of Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, 030001, People’s Republic of China; 3The Fifth Clinical Medical School of Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Ben Hu; Suyun Yang, Email a917744537@163.com; wangyan86@sxmu.edu.cnPurpose: This research sought to evaluate the clinical value of systemic immune-inflammation index and systemic inflammation response index in predicting the response to radioactive iodine (RAI) therapy in individuals diagnosed with differentiated thyroid cancer.Patients and Methods: This retrospective study included 406 patients with differentiated thyroid cancer who received initial RAI therapy and follow-up from December 2019 to December 2023. Patients were divided into two groups based on imaging and serum indicators to evaluate the response to radioactive iodine treatment: the ER group (excellent response) and the non-ER group (suboptimal response). Systemic immune-inflammation index and systemic inflammation response index were calculated based on peripheral blood cell counts before treatment. Multivariable logistic regression analysis was used to assess the independent associations of these indices with the therapeutic response to radioiodine treatment. Receiver operating characteristic (ROC) curves were graphed and the area under the curve (AUC) was calculated to evaluate their predictive ability.Results: Compared to the ER group, patients in the non-ER group had significantly elevated systemic immune-inflammation index and systemic inflammation response index levels (p < 0.001). After adjusting for confounding factors, there was a significant association between these indices and the response to radioactive iodine treatment in patients with differentiated thyroid cancer. The optimal cutoff values for predicting the response to RAI treatment were 668.91 for systemic immune-inflammation index (AUC=0.692, sensitivity 58.2%, specificity 73.1%, 95% CI: 0.639– 0.745, p < 0.001) and 0.47 for systemic inflammation response index (AUC=0.664, sensitivity 85.6%, specificity 42.7%, 95% CI: 0.612– 0.717, p < 0.001).Conclusion: Systemic immune-inflammation index and systemic inflammation response index could be valuable for predicting the response to RAI treatment in individuals diagnosed with differentiated thyroid cancer. Further research is needed to explore their practical utility, and these novel inflammation markers could serve as adjunct tools in clinical practice.Keywords: systemic immune-inflammation index, systemic inflammation response index, differentiated thyroid cancer, radioactive iodine therap

Background: Systemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes. Repeated or chronic systemic inflammation leads to a state of innate immune tolerance: a protective mechanism against over-activity of the immune system. In this study we investigated the immune adaptation of microglia and brain vascular endothelial cells in response to systemic inflammation or bacterial infection. Methods: Mice were given repeated doses of lipopolysaccharide (LPS) or a single injection of live Salmonella typhimurium. Inflammatory cytokines were measured in serum, spleen and brain, and microglial phenotype studied by immunohistochemistry.mice were infected with Salmonella typhimurium and subsequently challenged with a focal unilateral, intracerebral injection of LPS. Results: Repeated systemic LPS challenges resulted in increased brain IL-1?, TNF? and IL-12 levels, despite attenuated systemic cytokine production. Each LPS challenge induced significant changes in burrowing behaviour. In contrast, brain IL-1? and IL-12 levels in Salmonella typhimurium infected mice increased over three weeks, with high interferon-? levels in the circulation. Behavioural changes were only observed during the acute phase of the infection. Microglia and cerebral vasculature display an activated phenotype, and focal intracerebral injection of LPS 4 weeks after infection results in an exaggerated local inflammatory response when compared to non-infected mice. Conclusions: These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have aprofound effect on the onset and/ or progression of pre-existing neurodegenerative disease.Humans and animals are regularly exposed to bacterial and viral pathogens that can have a considerable impact on our day-to-day living [1]. Upon infection, a set of immune, physiological, metabolic, and behavioural responses is initiated, representing a highly organized strategy of the organism to fight infection. Pro-inflammatory mediators generated in peripheral tissue communicate with the brain to modify behaviour [2], which aids our ability to fight and eliminate the pathogen. The communication pathways from the site of inflammation to the brain have been investigated in animal models and systemic challenge with lipopolysaccharide (LPS) or double stranded RNA (poly I:C) have been widely used to mimic aspects of bacterial and viral infection respectively [3, 4]. These studies have provided evidence that systemically generated inflammatory mediators signal to the brain via both neural and humoral routes, the latter signalling via the circumventricular organs or across the blood-brain barrier (BBB). Signalling into the brain via these routes evokes a response in the perivascular macrophages (PVMs) and microglia, which in turn synthesise diverse inflammatory mediators including cytokines, prostaglandins and nitric oxide [2, 5, 6]. Immune-to-brain communication also occurs in humans who show changes in mood and cognition following systemic inflammation or infection, which are associated with changes in activity in particular regions of the CNS [7-9]. While these changes are part of our normal homeostasis, it is increasingly evident that systemic inflammation has a detrimental effect in animals and also humans, that suffer from chronic neurodegeneration [10, 11]. We, and others, have shown that microglia become primed by on-going neuropathology in the brain, which increases their response towards subsequent inflammatory stimuli, including systemic inflammation [12, 13] Similar findings have been made in aged rodents [14, 15], where it has been shown that there is an exaggerated behavioural and innate immune response in the brainto systemic bacterial and viral infections, but the molecular mechanisms underlying the microglial priming under these conditions is far from understood.Humans and animals are rarely exposed to a single acute systemic inflammatory event: they rather encounter infectious pathogens that replicate in vivo or are exposed to low concentrations of LPS over a prolonged period of time. There is limited information on the impact of non-neurotrophic bacterial infections on the CNS and whether prolonged systemic inflammation will give rise to either a hyper-(priming) or hypo-(tolerance) innate immune response in the brain in response to a subsequent inflammatory stimulus.In this study we measured the levels of cytokines in the serum, spleen and brain as well as assessing sickness behaviour following a systemic bacterial infection using attenuated Salmonella typhimurium SL3261: we compared the effect to that of repeated LPS injections. We show that Salmonella typhimurium caused acute, transient behavioural changes and a robust peripheral immune response that peaks at day 7. Systemic inflammation resulted in a delayed increase in cytokine production in the brain and priming of microglia, which persisted up to four weeks post infection. These effects were not mimicked by repeated LPS challenges. It is well recognised that systemic bacterial and viral infections are significant contributors to morbidity in the elderly [16], and it has been suggested that primed microglia play a role in the increased clinical symptoms seen in patients with Alzheimer’s disease who have systemic inflammation or infections [11, 17]. We show here that systemic infection leads to prolonged cytokine synthesis in the brain and also priming of brain innate immune cells to a subsequent focal inflammatory challenge in the brain parenchyma

Innate and adaptive immunity participate in and regulate numerous human diseases. Increasing evidence implies that metabolic reprogramming mediates immune cell functional changes during immune responses. In this review, we present and discuss our current understanding of metabolic regulation in different immune cells and their subsets in response to pathological stimuli. An interactive biochemical and molecular model was established to characterize metabolic reprogramming and their functional implication in anti-inflammatory, immune resolution, and proinflammatory responses. We summarize 2 major features of metabolic reprogramming in inflammatory stages in innate and adaptive immune cells: (1) energy production and biosynthesis reprogramming, including increased glycolysis and decreased oxidative phosphorylation, to secure faster ATP production and biosynthesis for defense response and damage repair and (2) epigenetic reprogramming, including enhanced histone acetylation and suppressed DNA methylation, due to altered accessibility of acetyl/methyl group donor and metabolite-modulated enzymatic activity. Finally, we discuss current strategies of metabolic and epigenetic therapy in cardiovascular disease and recommend cell-specific metabolic and gene-targeted site-specific epigenetic alterations for future therapies.

The lung is a primary organ for gas exchange in mammals that represents the largest epithelial surface in direct contact with the external environment. It also serves as a crucial immune organ, which harbors both innate and adaptive immune cells to induce a potent immune response. Due to its direct contact with the outer environment, the lung serves as a primary target organ for many airborne pathogens, toxicants (aerosols), and allergens causing pneumonia, acute respiratory distress syndrome (ARDS), and acute lung injury or inflammation (ALI). The current review describes the immunological mechanisms responsible for bacterial pneumonia and sepsis-induced ALI. It highlights the immunological differences for the severity of bacterial sepsis-induced ALI as compared to the pneumonia-associated ALI. The immune-based differences between the Gram-positive and Gram-negative bacteria-induced pneumonia show different mechanisms to induce ALI. The role of pulmonary epithelial cells (PECs), alveolar macrophages (AMs), innate lymphoid cells (ILCs), and different pattern-recognition receptors (PRRs, including Toll-like receptors (TLRs) and inflammasome proteins) in neutrophil infiltration and ALI induction have been described during pneumonia and sepsis-induced ALI. Also, the resolution of inflammation is frequently observed during ALI associated with pneumonia, whereas sepsis-associated ALI lacks it. Hence, the review mainly describes the different immune mechanisms responsible for pneumonia and sepsis-induced ALI. The differences in immune response depending on the causal pathogen (Gram-positive or Gram-negative bacteria) associated pneumonia or sepsis-induced ALI should be taken in mind specific immune-based therapeutics.

Inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, and leukotrienes, impact the immune system, usually as proinflammatory factors. Other mediators act as regulatory components to establish homeostasis after injury or prevent the inflammatory process. Histamine, a biogenic vasoactive amine, causes symptoms such as allergies and has a pleiotropic effect that is dependent on its interaction with its four histamine receptors. In this review, we discuss the dualistic effects of histamine: how histamine affects inflammation of the immune system through the activation of intracellular pathways that induce the production of inflammatory mediators and cytokines in different immune cells and how histamine exerts regulatory functions in innate and adaptive immune responses. We also evaluate the interactions between these effects.

Aims: The aim of this study was to develop easily applicable tools that reflect systemic inflammation in rheumatoid arthritis (RA). In this context, the relationship between RA disease activity and pan-immune-inflammation value (PIV), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI) was examined. Methods: Patients and healthy controls who applied to Yozgat Bozok University Physical Medicine and Rehabilitation and Internal Medicine clinics between 01.01.2020 and 04.01.2025 were included in the study. Visual Analog Scale (VAS), Disease Activity Score-28 (DAS28), hemogram, and biochemistry parameters—including ALT, AST, fasting glucose, C-reactive protein (CRP), erythrocyte sedimentation rate, uric acid, creatinine, calcium, magnesium, alkaline phosphatase, parathyroid hormone, lipid profile, albumin, total protein, T4, TSH, rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP)—were retrospectively recorded from patient files. PIV, SII, and SIRI were calculated using complete blood count data from both the RA and control groups. Data were analyzed using SPSS, and a significance level of 0.05 was considered statistically significant. Results: SII, SIRI, and PIV values were significantly higher in the RA group compared to the control group (p=0.002, p=0.001, and p=0.001, respectively). Among the three disease activity groups, SII, SIRI, and PIV levels were highest in the active disease group. A positive correlation was found between DAS28 and SII (r=0.305, p=0.012), and between DAS28 and PIV (r=0.270, p=0.028). However, no significant correlation was observed between DAS28 and SIRI (p=0.111). The difference among the activity groups was statistically significant for SII and PIV (p=0.016 and p=0.039, respectively), but not for SIRI (p=0.171). Furthermore, SII and PIV levels were significantly higher in patients receiving anti-TNF-? treatment compared to those using DMARDs (p=0.001 and p=0.003, respectively). Conclusion: The significantly higher SII and PIV values in the RA group compared to controls, and their positive correlation with DAS28, suggest that these indices may be associated with RA disease activity. Additionally, the lower levels of SII and PIV in patients receiving anti-TNF-? treatment support their potential role in monitoring treatment response.

Chitin, after cellulose the second most abundant polysaccharide in nature, is an essential component of exoskeletons of crabs, shrimps and insects and protects these organisms from harsh conditions in their environment. Unexpectedly, chitin has been found to activate innate immune cells and to elicit murine airway inflammation. The skin represents the outer barrier of the human host defense and is in frequent contact with chitin-bearing organisms, such as house-dust mites or flies. The effects of chitin on keratinocytes, however, are poorly understood. We hypothesized that chitin stimulates keratinocytes and thereby modulates the innate immune response of the skin. Here we show that chitin is bioactive on primary and immortalized keratinocytes by triggering production of pro-inflammatory cytokines and chemokines. Chitin stimulation further induced the expression of the Toll-like receptor (TLR) TLR4 on keratinocytes at mRNA and protein level. Chitin-induced effects were mainly abrogated when TLR2 was blocked, suggesting that TLR2 senses chitin on keratinocytes. We speculate that chitin-bearing organisms modulate the innate immune response towards pathogens by upregulating secretion of cytokines and chemokines and expression of MyD88-associated TLRs, two major components of innate immunity. The clinical relevance of this mechanism remains to be defined

Aims: Acute pancreatitis (AP) is an inflammatory disease with a wide clinical spectrum ranging from mild self-limited inflammation to severe life-threatening complications. Early identification of disease severity is essential for appropriate clinical management. Recently, novel inflammatory indices derived from routine hematological parameters, including the Systemic Immune-Inflammation Index (SII), Systemic Inflammation Response Index (SIRI), and Pan-Immune Inflammation Value (PIV), have been proposed as potential biomarkers reflecting systemic inflammatory status. This study aimed to evaluate the diagnostic and prognostic value of SII, SIRI, and PIV in patients with acute pancreatitis. Methods: This retrospective observational study included 101 patients diagnosed with acute pancreatitis and 118 healthy controls. Demographic, clinical, and laboratory data were obtained from the hospital electronic medical record system. Laboratory parameters including white blood cell count, neutrophils, lymphocytes, platelets, C-reactive protein, serum amylase, and lipase were analyzed. SII, SIRI, and PIV values were calculated using standard formulas derived from peripheral blood cell counts. Group comparisons were performed using appropriate statistical tests, and receiver operating characteristic (ROC) curve analysis was conducted to determine the diagnostic performance of inflammatory indices. A p value <0.05 was considered statistically significant. Results: Serum amylase, lipase, WBC count, neutrophil count, NLR, CRP, and inflammatory indices (SII, SIRI, and PIV) were significantly higher in patients with acute pancreatitis compared with the control group (p<0.05). ROC curve analysis demonstrated that these indices had strong diagnostic performance. Among the evaluated parameters, PIV showed the highest diagnostic accuracy with an area under the curve (AUC) of 0.895, followed by SIRI (AUC=0.890), SII (AUC=0.831), and NLR (AUC=0.823). Conclusion: SII, SIRI, and PIV are practical and cost-effective biomarkers derived from routine laboratory parameters that may aid in the early diagnosis and prognostic evaluation of acute pancreatitis. These indices may help clinicians assess systemic inflammatory response and identify high-risk patients in the early stage of the disease. Further prospective multicenter studies are needed to confirm their clinical utility.

Background Bacterial DNA containing motifs of unmethylated CpG dinucleotides (CpG-ODN) initiate an innate immune response mediated by the pattern recognition receptor Toll-like receptor 9 (TLR9). This leads in particular to the expression of proinflammatory mediators such as tumor necrosis factor (TNF-alpha) and interleukin-1beta (IL-1beta). TLR9 is expressed in human and murine pulmonary tissue and induction of proinflammatory mediators has been linked to the development of acute lung injury. Therefore, the hypothesis was tested whether CpG-ODN administration induces an inflammatory response in the lung via TLR9 in vivo. Methods Wild-type (WT) and TLR9-deficient (TLR9-D) mice received CpG-ODN intraperitoneally (1668-Thioat, 1 nmol/g BW) and were observed for up to 6 hrs. Lung tissue and plasma samples were taken and various inflammatory markers were measured. Results In WT mice, CpG-ODN induced a strong activation of pulmonary NFKB as well as a significant increase in pulmonary TNF-alpha and IL-1beta mRNA/protein. In addition, cytokine serum levels were significantly elevated in WT mice. Increased pulmonary content of lung myeloperoxidase (MPO) was documented in WT mice following application of CpG-ODN. Bronchoalveolar lavage (BAL) revealed that CpG-ODN stimulation significantly increased total cell number as well as neutrophil count in WT animals. In contrast, the CpG-ODN-induced inflammatory response was abolished in TLR9-D mice. Conclusion This study suggests that bacterial CpG-ODN causes lung inflammation via TLR9

The aim of the experiment was to determine the effects of 2 different fat supplementations on immune functions of dairy cows under high ambient temperatures. The experiment involved 24 Italian Friesian cows, divided into 3 groups of 8 animals, that were subjected to fat supplementations based on whole flaxseed (FS) or microencapsulated fish oil (FO). At d 0, 45, and 90 of the experiment, lymphocyte response to phytohemagglutinin (PHA) was determined in vivo on each animal by measurement of skin-fold thickness at the site of PHA injection. A humoral response to chicken egg albumin (OVA) was established following a subcutaneous injection with OVA. To assess cows' immune responses, plasma was prepared from experimental blood samples taken at d 0, 15, 30, 45, 60, 75, and 90 of the experiment. Plasma samples were measured for the presence of anti-OVA IgG, IL-1beta, IL-6, and IL-10. Results revealed greater skin-fold thickness in cows fed FS compared with the FO and the control groups, corresponding to higher mean lymphocyte proliferation following in vivo PHA injection. Cows fed FS displayed higher titers of anti-OVA IgG than the control and FO-fed cows. No effects of the diet on IL-1beta or IL-6 were found, whereas IL-10 secretion was lower in FS-fed cows than in control cows. The present study demonstrates that feed supplementation of n-3 polyunsaturated fatty acids can enhance immune responses of dairy cows exposed to high ambient temperatures

Several chronic infections known to be associated with malignancy have established oncogenic properties. However the existence of chronic inflammatory conditions that do not have an established infective cause and are associated with the development of tumours strongly suggests that the inflammatory process itself provides the prerequisite environment for the development of malignancy. This environment includes upregulation of mediators of the inflammatory response such as cyclo-oxygenase (COX)-2 leading to the production of inflammatory cytokines and prostaglandins which themselves may suppress cell mediated immune responses and promote angiogenesis. These factors may also impact on cell growth and survival signalling pathways resulting in induction of cell proliferation and inhibition of apoptosis. Furthermore, chronic inflammation may lead to the production of reactive oxygen species and metabolites such as malondialdehyde within the affected cells that may in turn induce DNA damage and mutations and, as a result, be carcinogenic. Here it is proposed that the conditions provided by a chronic inflammatory environment are so essential for the progression of the neoplastic process that therapeutic intervention aimed at inhibiting inflammation, reducing angiogenesis and stimulating cell mediated immune responses may have a major role in reducing the incidence of common cancers. © 2001 Cancer Research Campaign http://www.bjcancer.com

Introduction This study aimed to investigate the relationship between the pan-immune-inflammation value (PIV), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI) and disease activity in rheumatoid arthritis (RA), characterized by chronic inflammation and immune system involvement, and to provide new insights into the clinical implications of RA. Material and methods A total of 148 participants, including 97 RA patients (both newly diagnosed and established cases) and 51 healthy controls, were included in the study. Disease severity was assessed using the Disease Activity Score 28 (DAS28), and the relationship between DAS28 and PIV, SII, and SIRI, obtained from complete blood count results, was investigated. Additionally, C-reactive protein and erythrocyte sedimentation rate measurements were included in the study. Results The average age of RA patients was significantly higher than that of healthy individuals (<i>p</i> = 0.002). A positive correlation was found between the DAS28 score and the inflammation indices (SII, PIV, SIRI), with 65.98% of RA patients in the active phase and 34.02% in remission. Systemic immune-inflammation index had a predictive accuracy of 75.26%, PIV 71.13%, and SIRI 72.16%. The AUC (area under curve) values for SII, PIV, and SIRI were 0.717, 0.719, and 0.717, respectively, with cutoff values of 611.45, 323.88, and 1.18. Sensitivity and specificity were calculated as 57.81% and 60.61% for SII, 60.94% and 63.64% for PIV, and 59.38% and 63.64% for SIRI. Conclusions The findings revealed that PIV, SII, and SIRI were elevated in individuals with RA and may serve as complementary diagnostic markers. PIV, SII, and SIRI, as measures of disease activity in RA, may help monitor treatment efficacy and improve patient prognosis.