Search

Exposure to air particulate matter (PM) is linked to the blood oxidative stress and systemic inflammation. The aim of this study was to elucidate whether oxidative PM modification of ovalbumin (OVA), the major antioxidant serum protein, may alter its antigenicity and/or immunogenicity. Ovalbumin was exposed via dialysis to the standard urban PM (SRM 1648a) or to PM with removed organic content (encoded as LAP). Both structural changes and biological properties of PM-modified OVA were measured. T lymphocytes and dendritic cells (the major antigen-presenting cells) isolated from C57BL/6 and OT-II (323–339 epitope) OVA-specific T cell receptor (TCR)-transgenic mice were used to test the effect of PM on OVA immunogenicity. The immunogenicity of both SRM 1648a and LAP-modified OVA was significantly higher than that of control OVA, as measured by the epitope-specific T cell proliferation and interferon γ production by the stimulated cells. This effect was associated with mild oxidative changes in the carrier molecule outside the structure of the OVA epitope and with increased resistance to proteolysis of PM-modified OVA. Interestingly, dendritic cells showed enhanced capacity for the uptake of proteins when the cells were cultured with PM-modified OVA. Our results suggest that the enhanced immunogenicity of PM-modified OVA is not associated with altered antigenicity or antigen presentation. However, it may result from slower degradation and longer persistence of modified antigens in dendritic cells. Whether this phenomenon is associated with enhanced risk prevalence of autoimmune diseases observed in the areas with high urban PM pollution needs to be explained.

The role of chronic inflammatory process in the pathogenesis or exacerbation of hypertension has been already acknowledged.Therefore, one can speculate that hypotensive drugs may exert some of their therapeutic effects due to immunomodulatory properties. So far, this assumption has been tested in different studies, and the resulting knowledge is summarized in the current review article that is dedicated to different groups of antihypertensives, namely calcium channel blockers, beta blockers, as well as other less commonly used medications, such as hydralazine, alfa-2 receptor agonists, diazoxide, doxazosin, aliskiren, and sodium nitroprusside. Articles were found in the Pubmed by entering the name of a specific drug/group of drugs with the words: immunology, cellular response, humoral response, inflammation, interleukin. The 2000-2021 range was used to search for all drugs except propranolol (1980-2021) and calcium blockers (1990-2021).Observed decrease in serum/plasma concentration of proinflammatory cytokines, and CRP along with lower expression of adhesion molecules on immune cells strongly suggest that these drugs possess immunomodulatory properties, which seems to be crucial in the medical practice, especially in the therapy of hypertensive patients with other accompanying inflammatory-based diseases, such as type II diabetes, developed metabolic syndrome, allergies or autoimmunity.

Advanced cystic fibrosis (CF) lung disease is commonly characterized by a chronic Pseudomonas aeruginosa infection and destructive inflammation caused by neutrophils. However, the lack of convincing evidence from most informative biomarkers of severe lung dysfunction (SLD-CF) has hampered the formulation of a conclusive, targeted diagnosis of CF. The aim of this study was to determine whether SLD-CF is related to the high concentration of sputum inflammatory mediators and the presence of biofilm-forming bacterial strains. Forty-one patients with advanced CF lung disease were studied. The severity of pulmonary dysfunction was defined by forced expiratory volume in 1 second (FEV1)

Air pollution is considered to be one of a risk factor for rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) is commonly used as a mouse model of human RA. However, the impact of specific particulate matter (PM) components on the incidence and severity of RA has still not been established. The aim of this study was to develop an experimental model of CIA suitable to test arthritogenicity of inhaled PM. A mild form of CIA was induced in DBA1/J mice inhaled with various components of SRM 1648a PM. The incidence and severity of arthritis was assessed, and the selected serum markers of autoimmunity and inflammation were determined. Clinical arthritis was observed from the booster CII immunisation onward. Anti-cyclic citrullinated peptide antibodies, a diagnostic marker of RA, were detected in serum of these mice. All inhaled pollutants, crude PM, PM with reduced organic content, ferric, and silica nanoparticles markedly increased CIA incidence and severity. The fastest progression of CIA development was caused by crude PM and was linked to enhanced serum levels of anti-CII IgG, the prominent arthritogenic autoantibodies. On the other hand, inhaled nanoparticles enhanced serum levels of TNFα, a major proinflammatory arthritogenic cytokine. We recommend this experimental model of mild CIA to test the mechanisms of arthritis exacerbation by inhaled air pollutants. Further studies are necessary to determine whether PM-aggravated arthritis is caused by inflammatory mediators translocated from inflamed lung into systemic circulation or whether PM translocated into the bloodstream directly exacerbate joint inflammation.

Taurine haloamines, N-chlorotaurine (NCT, TauCl), and N-bromotaurine (NBT, TauBr) are formed by a reaction between taurine and hypohalous acids, HOCl and HOBr, respectively. The major source of endogenous taurine haloamines is neutrophils. Both NCT and NBT share strong anti-inflammatory and microbicidal activities supported by an absence of microbial resistance. In the light of these properties, a number of clinical studies have been performed to document their effectiveness in treatment of bacterial, fungal, and viral infections. The administration of NCT and NBT has been limited to topical application, as they are decomposed upon systemic delivery. This review summarizes current knowledge concerning the therapeutic use of NCT and NBT mainly in various skin disorders such as non-healing wounds, acne vulgaris, herpes zoster, and psoriasis. Moreover, the beneficial effect of NCT inhalation in early stages of COVID-19 and other viral respiratory infections is discussed. And finally, we would like to suggest that NCT might be used to inhibit the development of the cytokine storm through its capacity to suppress the production of IL-6.

Psoriasis is a chronic skin auto-inflammatory and systemic disorder. Novel treatments are needed to solve a plethora of cases refractory to current treatment regimens. N-bromotaurine (TauNH-Br), a natural taurine oxidizing derivative produced by inflammatory cells, has anti-inflammatory, antiproliferative, and antimicrobial properties. This evidence prompted us to use TauNH-Br as a local agent for treatment of therapy-refractory psoriasis. Two pustular-plaque psoriasis cases, unresponsive to systemic and local treatments, one with localized lesions and one with generalized lesions, were selected. Both applications primarily indicated a sufficient curative activity of 1% TauNH-Br in psoriasis lesions. Moreover, TauNH-Br co-administration with taurine and a novel olive oil formulation cut in half the time needed for TauNH-Br alone to cause the same regression of equivalent psoriasis plaque lesions in the same patient. Importantly, all adverse effects of TauNH-Br (erythema, itching, bleeding) could be minimized by the combination therapy. Periods of 2-7 weeks to achieve almost complete regression with this formulation were remarkably short as compared to conventional treatment regimens that both patients had followed previously. Of note, there was no relapse within 3 months of monitoring. Combination formulations containing TauNH-Br and olive oil could become an advantageous topical medication for treatment of psoriasis.

This review article is focused on antihypertensive drugs, namely angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), and their immunomodulatory properties reported in hypertensive patients as well as in experimental settings involving studies on animal models and cell lines. The immune regulatory action of ACEI and ARB is mainly connected with the inhibition of proinflammatory cytokine secretion, diminished expression of adhesion molecules, and normalization of CRP concentration in the blood plasma. The topic has significant importance in future medical practice in the therapy of patients with comorbidities with underlying chronic inflammatory responses. Thus, this additional effect of immune regulatory action of ACEI and ARB may also benefit the treatment of patients with metabolic syndrome, allergies, or autoimmune disorders.

Hypertension is a chronic disease associated with chronic inflammation involving activated macrophages. Antihypertensive drugs (for example, angiotensin-converting enzyme inhibitors—ACEIs) used in the treatment of hypertension have immunomodulatory properties. On the other hand, the immunological effect of diuretics and combined drugs (diuretics + ACEI) is unclear. Therefore, we examined the influence of diuretics and combination drugs (ACEI + diuretic) on cellular response (contact hypersensitivity), production of reactive oxygen intermediates (ROIs), and nitric oxide (NO), and the secretion of interleukin-12 (IL-12). CBA mice were administered i.p. captopril (5 mg/kg) with or without hydrochlorothiazide (10 mg/kg) or furosemide (5 mg/kg) for 8 days. On the third day, the mice were administered i.p. mineral oil, and macrophages were collected 5 days later. In the presented results, we show that diuretics administered alone or with captopril increase the generation of ROIs and reduce the formation of NO by macrophages. Moreover, tested drugs inhibit the secretion of IL-12. Diuretics and combined drugs reduce the activity of contact hypersensitivity (both activation and induction phases). Our research shows that the tested drugs modulate the cellular response by influencing the function of macrophages, which is important in assessing the safety of antihypertensive therapy.

Hypertension is accompanied by the over-activation of macrophages. Diuretics administered alone or in combination with hypotensive drugs may have immunomodulatory effects. Thus, the influence of tested drugs on mouse macrophage-mediated humoral immunity was investigated. Mice were treated intraperitoneally with captopril (5 mg/kg) with or without hydrochlorothiazide (10 mg/kg) or furosemide (5 mg/kg) by 8 days. Mineral oil-induced peritoneal macrophages were harvested to assess the generation of cytokines in ELISA, and the expression of surface markers was analyzed cytometrically. Macrophages were also pulsed with sheep red blood cells (SRBC) and transferred to naive mice for evaluation of their ability to induce a humoral immune response. Tested drugs increase the expression of surface markers important for the antigen phagocytosis and presentation. SRBC-pulsed macrophages from mice treated with captopril combined with diuretics increased the secretion of antigen-specific antibodies by recipient B cells, while macrophages of mice treated with hydrochlorothiazide or furosemide with captopril increased the number of antigen-specific B cells. Tested drugs alter the macrophage secretory profile in favor of anti-inflammatory cytokines. Our results showed that diuretics with or without captopril modulate the humoral response by affecting the function of macrophages, which has significant translational potential in assessing the safety of antihypertensive therapy.

We present a case of a 91-year-old female with stage 5 renal disease, diabetes type 2, and considerable weakness, suffering from a 2-month-old wound infected by a multiresistant Staphylococcus aureus. The wound measured 7 cm in length, 5 cm in width, and 1.5 cm in depth, having purulent white edges and exudates exceeding the size of the wound. The systemic antibiotic use was opposing to improve the patient’s clinical condition due to underlying nephrotoxicity that may have deteriorated renal failure and resistance of the infecting pathogen. The halogenated taurine (Tau) derivatives N-chlorotaurine (NCT) and N-bromotaurine (NBrT) with potent anti-inflammatory and antimicrobial efficacy were alternatively employed as combination topical treatment to provide a therapeutic solution. Each agent was applied separately with an interval of 5 minutes as a 1% spray in aqueous solution every 30 minutes during the day for 3 days. This treatment was very well tolerated and led to rapid disappearance of the purulent exudate, rapid epithelialization, and complete healing. To avoid relapse, the application was continued 4 times daily for a further 4 days. No complications occurred in the course of treatment. This case report confirms the therapeutic efficacy of NCT in chronic purulent wounds. NBrT is well tolerated, too, and can be used in combination with NCT in emergency clinical settings. Its potential as a single agent should be investigated in further studies. Advancement of wound closure by these agents proved to be life-saving for this patient. Further molecular research is needed to identify mechanisms that promote wound healing.

Microbial species can act in synergy to circumvent environmental stress conditions and survive. In addition, biofilms are a serious public-health issue globally and constitute a clinical emergency. Infection persistence, increased morbidity and mortality, and antibiotic resistance are consequences of poly-microbial synergy. Due to inherited complexity and synergy between numerous species, newer antimicrobial agents of increased efficacy and tolerability are needed. In this unique medical case, a chronic (9 year) multi-bacterial scalp infection was differentially diagnosed from other inflammatory skin disorders by prolonged microbiological culture. The bacterial species found seem to have caused lesions of visible biofilm not documented previously in the medical literature. This complicated infection was treated successfully and rapidly with the combined topical application of the active halogen compounds N-chlorotaurine, N-bromotaurine and bromamine T, which is in contrast to the previous failed systemic and topical therapeutic approaches. This study strengthens the case for the use of active halogen compounds against multi-bacterial infections of the skin in the future, without the occurrence of resistance.

Exopolysaccharides (EPSs), major components of the bacterial biofilm, display strong strain-specific immunomodulatory properties. Previously, we have shown that crude EPS derived from Lactobacillus rhamnosus KL37 depresses the production of arthritogenic anti-collagen IgG and ameliorates collagen-induced arthritis (CIA) in DBA/1 mice, when lipopolysaccharide (LPS) was used as adjuvant. In this study, we used highly purified EPS from L. rhamnosus KL37 (EPS-37) to verify its anti-inflammatory properties and the ability to suppress T cell-dependent humoral response. We have employed the model of active CIA, in which mice immunized with type II collagen (CII) along with LPS were treated with pure EPS-37. Intravenous administration of purified EPS-37 markedly ameliorated arthritis and reduced CII-specific antibody production. EPS-37 injected subcutaneously reduced the clinical symptoms of CIA but without the reduction of arthritogenic antibodies. In addition, the effect of EPS-37 on T-cell functions was tested ex vivo and in vitro. EPS-37 inhibited the in vitro proliferation of T cells activated both in vivo (CII immunization) and in vitro (antigen/mitogen), and markedly reduced the production of interferon (IFN)-γ. These results together with other reports suggest that anti-inflammatory potential of EPS-37 depends on its ability to inhibit either one or the other or both possible inflammatory signaling pathways. Namely, Th1 → IFN-γ → M1 inflammatory macrophages → arthritis and/or Th1 → IFN-γ → B cells → arthritogenic antibodies → arthritis. We suggest that L. rhamnosus KL37 EPS might be utilized to control T cell-dependent immune responses in various inflammatory diseases. However, the most effective route of EPS-37 administration needs to be tailored for a given disorder.

Taurine haloamines (N-chlorotaurine, N-bromotaurine) due to their strong antiseptic and anti-inflammatory properties are good candidates for topical application in treatment of skin inflammatory/infectious disorders. Recently, we have demonstrated that more stable N-bromotaurine analogs (N-dibromo-dimethyl taurine, N-monobromo-dimethyl taurine) and bromamine T show strong microbicidal and anti-inflammatory properties at concentrations well tolerated by human cells and tissue. Non-steroidal anti-inflammatory drugs (NSAIDs) with cyclooxygenase (COX) inhibitory activity are commonly used in various inflammatory diseases. However, systemic administration of NSAIDs may result in adverse side effects. For example, the use of ibuprofen in children with varicella is associated with enhanced serum levels of TNF-α and with increased risk of necrotizing soft tissue infections and secondary skin infections caused by invasive streptococci. The aim of this study was to examine combined immunomodulatory effects of bromamines and ibuprofen on J774.A1 macrophages. We have shown that the primary activity of ibuprofen, the inhibition of PGE2 production by activated macrophages was intensified in the presence of bromamines. Most importantly, the stimulatory effect of ibuprofen on production of inflammatory cytokines (TNF-α, IL-6) was inhibited by all tested bromamines. These observations indicate that bromamines may neutralize massive production of TNF-α at sites of inflammation, a side effect of ibuprofen. Therefore, we suggest that systemic administration of ibuprofen (NSAIDs) in treatment of inflammatory/infectious skin diseases should be supported by topical application of bromamines as an adjunctive therapy.

The stable N-bromotaurine analogs (N-dibromo-dimethyl taurine, N-monobromo-dimethyl taurine), and bromamine T (BAT) show anti-inflammatory and microbicidal properties. These bromamines are good candidates for a treatment of skin infectious/inflammatory diseases as local antiseptics. Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), is commonly used in various infectious/inflammatory diseases due to its analgesic and antipyretic therapeutic effects. However, systemic administration of ibuprofen may also result in adverse side effects. It has been reported that ibuprofen enhances serum levels of TNF-α and worsens secondary skin infections caused by invasive streptococci (S. pyogenes). Recently we have demonstrated that bromamines inhibit the stimulatory effect of ibuprofen on the production of inflammatory cytokines (TNF-α, IL-6). The aim of this study was to examine the combined antibacterial actions of ibuprofen and bromamines against S. pyogenes and their joint effect on the generation of reactive oxygen species (ROS) by activated neutrophils and macrophages. We have shown that the microbicidal activity of bromamines against S. pyogenes was not altered by ibuprofen. On the other hand, co-administration of ibuprofen and bromamines markedly decreased the generation of ROS by activated neutrophils and macrophages. Finally, we discuss how the antioxidant combined effect of bromamines and ibuprofen may affect a local defense system.

We present a case of a 91-year-old female with stage 5 renal disease, diabetes type 2, and considerable weakness, suffering from a 2-month-old wound infected by a multiresistant

Translocation of bacteria, primarily Gram-negative pathogenic flora, from the intestinal lumen into the circulatory system leads to sepsis. In newborns, and especially very low birth weight infants, sepsis is a major cause of morbidity and mortality. The results of recently conducted clinical trials suggest that lactoferrin, an iron-binding protein that is abundant in mammalian colostrum and milk, may be an effective agent in preventing sepsis in newborns. However, despite numerous basic studies on lactoferrin, very little is known about how metal saturation of this protein affects a host's health. Therefore, the main objective of this study was to elucidate how iron-depleted, iron-saturated, and manganese-saturated forms of lactoferrin regulate intestinal barrier function via interactions with epithelial cells and macrophages. For these studies, a human intestinal epithelial cell line, Caco-2, was used. In this model, none of the tested lactoferrin forms induced higher levels of apoptosis or necrosis. There was also no change in the production of tight junction proteins regardless of lactoferrin metal saturation status. None of the tested forms induced a pro-inflammatory response in Caco-2 cells or in macrophages either. However, the various lactoferrin forms did effectively inhibit the pro-inflammatory response in macrophages that were activated with lipopolysaccharide with the most potent effect observed for apolactoferrin. Lactoferrin that was not bound to its cognate receptor was able to bind and neutralize lipopolysaccharide. Lactoferrin was also able to neutralize microbial-derived antigens, thereby potentially reducing their pro-inflammatory effect. Therefore, we hypothesize that lactoferrin supplementation is a relevant strategy for preventing sepsis.

The stable N-bromotaurine analogs (N-dibromo-dimethyl taurine, N-monobromo-dimethyl taurine), and bromamine T (BAT) show anti-inflammatory and microbicidal properties. These bromamines are good candidates for a treatment of skin infectious/inflammatory diseases as local antiseptics. Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), is commonly used in various infectious/inflammatory diseases due to its analgesic and antipyretic therapeutic effects. However, systemic administration of ibuprofen may also result in adverse side effects. It has been reported that ibuprofen enhances serum levels of TNF-α and worsens secondary skin infections caused by invasive streptococci (S. pyogenes). Recently we have demonstrated that bromamines inhibit the stimulatory effect of ibuprofen on the production of inflammatory cytokines (TNF-α, IL-6). The aim of this study was to examine the combined antibacterial actions of ibuprofen and bromamines against S. pyogenes and their joint effect on the generation of reactive oxygen species (ROS) by activated neutrophils and macrophages. We have shown that the microbicidal activity of bromamines against S. pyogenes was not altered by ibuprofen. On the other hand, co-administration of ibuprofen and bromamines markedly decreased the generation of ROS by activated neutrophils and macrophages. Finally, we discuss how the antioxidant combined effect of bromamines and ibuprofen may affect a local defense system.

Murine macrophages of the J774A.1 line are hydrogen sulphide-producing cells with the primary role of γ-cystathionase (CTH) and secondary role of 3-mercaptopyruvate sulfurtransferase (limited by cysteine availability) and with a negligible role of cystathionine β-synthase (CBS) in H2S generation. J774A.1 cells stimulation with lipopolysaccharide (LPS) or interferon-gamma (IFNγ) resulted in decreased H2S levels after 24 h of incubation; however, they were restored to the control level after 48 h. Negligible CBS expression and activity in J774A.1 cells can result in homocysteine availability for CTH-catalyzed, H2S-generating reactions. This was supported by an increased CTH expression (IFNγ, 24 h and 48 h, and LPS, 48 h) and activity (24 h, LPS) in the stimulated cells. The results confirm the suggested feedback regulation between CBS and CTH.

Objective Pseudomonas aeruginosa effectively facilitate resistance to phagocyte killing by biofilm formation. However,b the cross talk between biofilm components and phagocytes is still unclear. We hypothesize that a biofilm provides a concentrated extracellular source of LPS, DNA and exopolysaccharides (EPS), which polarize neighbouring phagocytes into an adverse hyperinflammatory state of activation. Methods We measured the release of a panel of mediators produced in vitro by murine neutrophils and macrophages exposed to various biofilm components of P. aeruginosa cultures. Results We found that conditioned media from a high biofilm-producing strain of P. aeruginosa, PAR5, accumulated high concentrations of extracellular bacterial LPS, DNA and EPS by 72 h. These conditioned media induced phagocytes to release a hyperinflammatory pattern of mediators, with enhanced levels of $TNF-\alpha$, IL-6, IL12p40, $PGE_{2}$ and NO. Moreover, the phagocytes also upregulated COX-2 and iNOS with no influence on the expression of arginase-1. Conclusions Phagocytes exposed to biofilm microenvironment, called by us biofilm-associated neutrophils/macrophages (BANs/BAMs), display secretory properties similar to that of N1/M1-type phagocytes. These results suggest that in vivo high concentrations of LPS and DNA, trapped in biofilm by EPS, might convert infiltrating phagocytes into cells responsible for tissue injury without direct contact with bacteria and phagocytosis.

Epithelial cells are one of the most actively cycling cells in a mammalian organism and therefore are prone to malignant transformation. Already during organogenesis, the connective tissue (mesenchyme) provides instructive signals for the epithelium. In an adult organism, the mesenchyme is believed to provide crucial regulatory signals for the maintenance and regeneration of epithelial cells. Here, we discuss the role of intestinal myofibroblasts, α-smooth muscle actin-positive stromal (mesenchymal) cells, as an important regulatory part of the intestinal stem cell niche. Better understanding of the cross-talk between myofibroblasts and the epithelium in the intestine has implications for advances in regenerative medicine, and improved therapeutic strategies for inflammatory bowel disease, intestinal fibrosis and colorectal cancer.

Taurine haloamines (N-chlorotaurine, N-bromotaurine) due to their strong antiseptic and anti-inflammatory properties are good candidates for topical application in treatment of skin inflammatory/infectious disorders. Recently, we have demonstrated that more stable N-bromotaurine analogs (N-dibromo-dimethyl taurine, N-monobromo-dimethyl taurine) and bromamine T show strong microbicidal and anti-inflammatory properties at concentrations well tolerated by human cells and tissue. Non-steroidal anti-inflammatory drugs (NSAIDs) with cyclooxygenase (COX) inhibitory activity are commonly used in various inflammatory diseases. However, systemic administration of NSAIDs may result in adverse side effects. For example, the use of ibuprofen in children with varicella is associated with enhanced serum levels of TNF-α and with increased risk of necrotizing soft tissue infections and secondary skin infections caused by invasive streptococci. The aim of this study was to examine combined immunomodulatory effects of bromamines and ibuprofen on J774.A1 macrophages. We have shown that the primary activity of ibuprofen, the inhibition of PGE2 production by activated macrophages was intensified in the presence of bromamines. Most importantly, the stimulatory effect of ibuprofen on production of inflammatory cytokines (TNF-α, IL-6) was inhibited by all tested bromamines. These observations indicate that bromamines may neutralize massive production of TNF-α at sites of inflammation, a side effect of ibuprofen. Therefore, we suggest that systemic administration of ibuprofen (NSAIDs) in treatment of inflammatory/infectious skin diseases should be supported by topical application of bromamines as an adjunctive therapy.

Objective: Enteric bacteria are involved in the pathogenesis of ulcerative colitis. in experimental colitis, a breakdown of the intestinal epithelial barrier results in inflow of various gut bacteria, induction of acute inflammation and finally, progression to chronic colitis. Material and methods: in the present study we compared pro-inflammatory properties of two bacterial strains isolated from human microbiome, Escherichia coli 3a1 and lactobacillus plantarum kl30B. the study was performed using two experimental models of acute inflammation: peritonitis in mice and trinitrobenzenesulfonic acid (tnBS)-induced colitis in rats. Results: Both bacterial strains induced massive neutrophil infiltration upon injection into sterile peritoneal cavity. However, peritoneal exudate cells stimulated in vitro with E. coli 3a1, produced far more nitric oxide, than those stimulated with l. plantarum kl30B. interestingly, distinct effect on the development of tnBS-induced colitis was observed after oral administration of the tested bacteria. lactobacillus plantarum kl30B evoked strong acute colitis. on the contrary, the administration of E. coli 3a1 resulted in a progression of colitis to chronicity. Conclusions: our results show that distinct effects of bacterial administration on the development of ongoing inflammation is strain specific and depends on the final effect of cross-talk between bacteria and cells of the innate immune system.

Objective Exposure to air particulate matter (PM) is associated with chronic inflammatory and autoimmune diseases. Macrophages are responsible for the regulation of chronic inflammation. However, whether PM affects macrophage polarization remains unclear. The aim of this study was to evaluate whether nontoxic concentrations of urban PM are able to prime macrophages to altered inflammatory response upon LPS challenge. Methods We used two forms of the urban particulate matter SRM 1648a, intact PM and PM deprived of organic compounds (PM$\Delta$C). Peritoneal murine macrophages were exposed to different concentrations of PM for 24 h and then challenged with LPS. Production of inflammatory mediators by macrophages was measured to test immunostimulatory/priming capacity of PM. Results Particulate matter used at non-cytotoxic concentrations induced a dose-dependent production of proinflammatory cytokines ($TNF-\alpha$, IL-6, IL-12p40). By contrast, PM$\Delta$ C were not able to stimulate macrophages. However, macrophages primed with both forms of PM show proinflammatory response upon LPS challenge. Conclusions Our data indicate that exposure of macrophages to low concentrations of PM may prime the cells to hyperinflammatory response upon contact with LPS. Further studies are necessary to explain whether the exposure of patients suffering from chronic inflammatory diseases to particulate matter is responsible for the exacerbation of clinical symptoms during bacterial infections.

For decades, neutrophils were generally regarded as the cells of innate immunity with proinflammatory and phagocytic properties involved in a dual activity, beneficial (antimicrobial) and detrimental (tissue damage). Importantly, until the discovery of toll-like receptors (TLRs), a role of neutrophils in adaptive immunity was limited to the effector stage of humoral response and phagocytosis of opsonized antigens. Moreover, in common opinion, neutrophils, as well as the entire innate immune system, were not functionally associated with adaptive immunity. At the time we demonstrated protein chlorination by HOCl, the major product of neutrophil MPO-halide system enhances protein immunogenicity. Based on this discovery, we proposed, as the first, a new role for neutrophils as APC-accessory cells involved in the induction stage of adaptive immunity. Thereafter, we developed our theory concerning the role of neutrophils as the cells which link innate and adaptive immunity. We proposed that protein modification by HOCl may act as a neutrophildependent molecular tagging system, by which sentinel dendritic cells can faster recognise pathogen- derived antigens. Contemporaneously, it was demonstrated that taurine, the most abundant free amino acid in neutrophil cytosol and the major scavenger of HOCl, is a part of the oxidantantioxidant network and is responsible for the regulation and termination of acute inflammation. Moreover, it has been described, that taurine chloramine (TauCl), the physiological products of the reaction of HOCl with taurine, show anti-microbial and anti-inflammatory properties. : In this review, the role of HOCl, taurine and TauCl in innate and adaptive immunity will be discussed.

A number of epidemiological studies have shown a strong association between exposure to ambient airborne particulate matter (PM 2.5, PM < 1.0) and lung or cardiovascular diseases characterised by high mortality and morbidity. However, much less is known about the role of air pollution in the pathogenesis of autoimmune diseases, which constitutes a significant problem in modern society. This paper summarises the state of current research regarding the influence of PM on the development and/or progression of autoimmune diseases. A brief review of the great body of research concerning pathogenesis of autoimmune disorders is presented. Then, the scope of our review is narrowed to the research related to the impact of particulate matter on oxidative and nitrosative stress, as well as exacerbation of chronic inflammation, because they can contribute to the development of autoimmune diseases. Moreover, we discuss the impact of various components of PM (metal, organic compounds) on PM toxicity and the ability to generate oxidants.

Macrophages are involved in various mechanisms of allergic and autoimmune response, especially in delayed-type hypersensitivity. Apart from antigen presentation, macrophages also act as effector cells in cellular hypersensitivity reaction induced by either pathogen during infection, hapten-antigen or self-antigen in pathological conditions. Their ability to secrete Th2-dependent cytokines as well as reactive oxygen and nitrogen intermediates exacerbates the severity of symptoms of allergy and asthma. Macrophage properties and activities could be modulated by numerous factors including drugs and biologically active compounds that may be used in future therapy. The present review is focused on the current knowledge about macrophage functions in allergy, autoimmunity and the mechanisms of their modulation.

SR-A/CD204 and CD36 are major receptors responsible for oxidized lipoproteins uptake by macrophages in atherosclerotic plaques. Both receptors also share the role as receptors for different pathogens, but studies on their signaling have been hampered by the lack of selective ligands. We report that, upon specific ligation by Ab, SR-A does not induce cytokine production, but mediates inhibition of LPS-stimulated production of IL-6 and IL-12/23p40, enhancement of IL-10 release, and has no effect on TNF-α and RANTES production in murine macrophages. In contrast, anti-CD36 Ab alone stimulated production of all these cytokines, with IL-10 production being exceptionally high. Effects of anti-CD36 Ab, except of IL-10 production, were mediated by CD14 and TLR2, whereas those of SR-A ligation by heterotrimeric Gi/o proteins and by phosphatidylinositol 3-kinases. Surprisingly, we found that LPS uptake by macrophages was mediated in part by CD36 cooperating with CD14, whereas SR-A was not involved in this process. Finely, during in vitro Ag presentation to naïve CD4+ lymphocytes, pre-incubation of macrophages with anti-CD36 Ab enhanced IFN-γ production in the co-culture, but exerted the opposite effect under conditions enabling IL-10 accumulation. In contrast, anti-SR-A Ab was ineffective alone, but reversed the Th1-polarizing effect of LPS.

Recent microbiological investigations completely changed our understanding of the role of biofilm in the formation of the mucosal immune barrier and in pathogenesis of chronic inflammation of bacterial etiology. It is now clear that formation of bacterial biofilm on dental surfaces is characteristic for existence of oral microbial communities. It has also been proved that uncontrolled biofilms on dental tissues, as well as on different biomaterials (e.g. orthodontic appliances), are the main cause of dental diseases such as dental caries and periodontitis. The aim of this paper is to explain mechanisms and consequences of orthodontic biofilm formation. We will discuss current opinions on the influence of different biomaterials employed for orthodontic treatment in biofilm formation and new strategies employed in prevention and elimination of oral biofilm ("dental plaque").

Taurine, the most abundant free amino acid in leukocyte cytosol traps hypohalous acids (HOCl and HOBr) to produce N-chlorotaurine (taurine chloramine, NCT and N-bromotaurine (taurine bromamine, Tau-NHBr,) respectively. Both haloamines show anti-inflammatory and antimicrobial properties. However, the therapeutic applicability of Tau-NHBr is limited due to its relatively poor stability. To overcome this disadvantage, we have synthesized the stable N-bromotaurine compounds N-monobromo-2,2-dimethyltaurine (Br-612) and N-dibromo-2,2-dimethyltaurine (Br-422). The aim of this study was to compare anti-inflammatory and microbicidal properties of Br-612 and Br-422 with that of Tau-NHBr and bromamine T (BAT). We have shown that all the tested compounds show similar anti-inflammatory properties. Importantly, the stable N-bromotaurine compounds exerted even stronger microbicidal activity than Tau-NHBr. Finally, for the purpose of topical application of these compounds we have developed a carbomer-based bioadhesive solid dosage form of BAT and Br-612, featuring sustained release of the active substance.

Scavenger receptor (SR)-mediated opsonin-independent phagocytosis of bacteria by macrophages has been suggested to represent an important, early mechanism of anti-bacterial host defense. However, although the ability to bind bacteria has been demonstrated to be a shared feature of all types of SRs, in many cases the evidence is limited to the demonstration of increased binding of killed, fluorescently labeled bacteria to non-phagocytic cells transfected with these receptors. We sought to verify the ability of SRs to mediate non-opsonic phagocytosis of live Escherichia coli (Ec) and Staphylococcus aureus (Sa), model species of Gram-negative and -positive bacteria, respectively, and to assess the relative contributions of different SRs expressed on murine macrophages in this process. We found that the class A SR SR-A/CD204 was the major receptor mediating phagocytosis of fluorescently labeled Sa, whereas different SRs had highly redundant roles in the phagocytosis of live Sa. Conversely, different SRs contributed to the phagocytosis of fluorescently labeled Ec. In comparison, phagocytosis of live Ec was of much lower magnitude and was selectively mediated by SR-A. These results question the use of fluorescently labeled bacteria as valid replacements for live bacteria. The low magnitude of opsonin-independent phagocytosis of Ec and unimpaired phagocytosis of Sa in SR-A- or CD36-deficient macrophages indicate that the defect in this process might not be responsible for the reported impaired bacteria clearance in mice deficient in these receptors. We postulate that this impairment might result to a larger extent from inhibition of intracellular bacteria killing caused by pro-inflammatory cytokines, produced in excessive amounts by SR-deficient cells in response to bacterial products.

Oral administration of some probiotic bacteria (e.g. Lactobacillus rhamnosus) attenuates various types of experimental arthritis, including collagen-induced arthritis (CIA) and inhibits arthritogenic autoantibodies. Much less is known about the possible anti-arthritogenic properties of exopolysaccharide (EPS), the major component of lactic bacteria biofilm. In this study, we asked the question whether systemic administration of EPS derived from L. rhamnosus KL37 depresses the production of anti-collagen IgG and affects the development of CIA in DBA/1 mice. Arthritis was induced employing two models of active CIA, in which mice were immunized with type II collagen (CII) either in the presence of lipopolysaccharide (LPS; mild arthritis with moderate CII-specific IgG production) or with Complete Freund's Adjuvant and LPS (severe arthritis with massive CII-specific IgG production). Passive CIA was induced by intravenous injection of CII-specific monoclonal antibodies and LPS. Disease progression, the incidence and severity of arthritis, were determined. Serum concentration of CII-specific IgG was measured by enzyme-linked immunosorbent assay. Systemic administration of EPS markedly reduced CII-specific antibody production. Moreover, EPS significantly ameliorated arthritis in the active models of CIA, especially, when LPS alone was used as an adjuvant. In contrast, when arthritogenic antibodies were injected to mice in high amounts, the effect of EPS on the development of passive CIA was negligible and transient. These results show that EPS can suppress active CIA by the inhibition of arthritogenic antibodies production. Therefore, we suggest that EPS or EPS-producing probiotics may be promising agents for the supporting therapy of patients with rheumatoid arthritis.

This report presents simple and reliable approach developed to study the specific recognition events between chlorinated ovalbumin (OVA) and macrophages using atomic force microscopy (AFM). Thanks to the elimination of nonspecific adhesion, the interactions of the native and chlorinated OVA with a membrane of macrophages could be quantified using exclusively the so-called adhesion frequency (AF). The proposed system not only enabled the application of AFM-based force measurements for such poorly defined ligand-receptor pairs but also significantly improved both the acquisition and the processing of the data. The proteins were immobilized on the gold-coated AFM tips from the aqueous solutions containing charged thiol adsorbates. Such surface dilution of the proteins ensured the presence of single or just a few macromolecules at the tip-surface contact. The formation of negatively charged monolayer on the tip dramatically limited its nonspecific interactions with the macrophage surface. In such systems, AF was used as a measure of the recognition events even if the interaction forces varied significantly for sets of measurements. The system with the native OVA, a weak immunogen, showed only negligible AF compared with 85% measured for the immunogenic chlorinated OVA. The AF values varied with the tip-macrophage contact time and loading velocity. Blocking of the receptors by the chlorinated OVA was also confirmed. The developed approach can be also used to study other ligand-receptor interactions in poorly defined biological systems with intrinsically broad distribution of the rupture forces, thus opening new fields for AFM-based recognition on molecular level.

Myeloperoxidase (MPO) is a major protein constituent of the primary granules of vertebrate neutrophils. It catalyses the hydrogen peroxide-mediated oxidation of halide ions to hypohalous acids, especially HOCl. These reactive oxygen species can participate in a variety of secondary reactions, leading to modifications of amino acids and many types of biological macromolecules. The classic paradigm views MPO as a component of the phagocyte oxygen-dependent intracellular microbicidal system, and thus an important arm of the effector phase of innate immune responses. However, the limited immunodeficiency associated with lack of MPO in mouse and human models has challenged this paradigm. In this review we examine more recent information on the interaction between MPO, its bioreactive reaction products, and targets within the inflammatory microenvironment. We propose that two assumptions of the current model may require revisiting. First, many important targets of MPO modification are extracellular, rather than present only within the phagolysosome, such as various components of neutrophil extracellular traps. Second, we suggest that the pro-inflammatory pathological role of MPO may be a particular feature of chronic inflammation. In the physiological setting of acute neutrophil-mediated inflammation MPO may also form part of a negative feedback loop which down-regulates inflammation, limits tissue damage, and facilitates the switch from innate to adaptive immunity. This different perspective on this well-studied enzyme may usefully inform further research into its function in health and disease.

Objectives Numerous receptors have been implicated in recognition of pathogenic fungi by macrophages, including the β-glucan receptor dectin-1. The role of scavenger receptors (SRs) in anti-fungal immunity is not well characterized. Methods We studied uptake of unopsonized Saccharomycetes cerevisiae (zymosan) and live Candida albicans yeasts as well as zymosan-stimulated H2O2 production in J774 macrophage-like cells and peritoneal exudate macrophages (PEMs). The role of different receptors was assessed with the use of competitive ligands, transfected cells and receptor-deficient macrophages. Results The uptake of zymosan by untreated J774 cells was mediated approximately half by SRs and half by a β-glucan receptor which was distinct from dectin-1 and not linked to stimulation of H2O2 production. Ligands of β-glucan receptors and of SRs also inhibited uptake of C. albicans by macrophages (J774 cells and PEMs). In macrophages pretreated with a CpG motif-containing oligodeoxynucleotide (CpG-ODN) the relative contribution of SRs to yeast uptake increased and that of β-glucan receptors decreased. Whereas the class A SR MARCO participated in the uptake of both zymosan and C. albicans by CpG-ODN-pretreated, but not untreated macrophages, the related receptor SR-A/CD204 was involved in the uptake of zymosan, but not of C. albicans. The reduction of zymosan-stimulated H2O2 production observed in DS-pretreated J774 cells and in class A SRs-deficient PEMs suggest that class A SRs mediate part of this process. Conclusions Our results revealed that SRs belong to a redundant system of receptors for yeasts. Binding of yeasts to different receptors in resting versus CpG-ODN-pre-exposed macrophages may differentially affect polarization of adaptive immune responses.

The ability to produce exopolysaccharides (EPS) is widespread among lactobacilli including Lactobacillus rhamnosus, the commonly used probiotic bacteria. Exopolysaccharides are a major component of the bacterial biofilm with a well-documented impact on adherence of bacteria to host cells. However, their immunoregulatory properties are unknown. The aim of this study was to examine the immunostimulatory potential of EPS derived from L. rhamnosus KL37. We investigated the effect of EPS on the production of inflammatory mediators by mouse peritoneal macrophages and compared it with the effect of Lipopolysaccharide (LPS). Exopolysaccharides, at concentrations higher than those of LPS, stimulated production of both pro-inflammatory (TNF-α, IL-6, IL-12) and anti-inflammatory (IL-10) cytokines. Interestingly, analysis of the balance of TNF-α/IL-10 production showed a potential pro-inflammatory effect of EPS. Furthermore, our data demonstrate that exposure of macrophages to LPS induced a state of hyporesponsiveness, as indicated by reduced production of TNF-α after restimulation with either LPS or EPS (‘cross-tolerance’). By contrast, EPS could make cells tolerant only to subsequent stimulation by the same stimulus. We also examined the relationship between TNF-α production and activation of mitogen-activated protein kinases (MAPKs) by EPS and LPS. Pretreatment of macrophages with specific inhibitors of p38 and ERK MAPKs reduced TNF-α production induced by both stimuli to the same extent. In conclusion, these data demonstrate that EPS can effectively stimulate production of inflammatory mediators by macrophages in vitro. However, to predict whether EPS could be clinically useful as an immunomodulatory agent, further in vivo studies with highly purified EPS are necessary.

Myeloid-derived suppressor cells are important cell population with an immunoregulatory potential in both adaptive and innate immunity. Their immunosuppressive activity is widely accepted. However, emerging evidence suggests that this heterogeneous cell population can be, under some circumstances, immunostimulatory rather than suppressive. This finding can shed a new light on antitumour immunity which is believed to be impaired in immunosuppressive environments.

Acne vulgaris is a multifactorial inflammatory skin disease. One of the pathogenic factors in acne is Propionibacterium acnes (P. acnes). Traditional treatment of acne lesions involves topical application of antibiotics with anti-bacterial and anti-inflammatory properties. However, a failure of this therapy is widely associated with emergence of resistant bacteria. Therefore, a search for alternative topical anti-acne drugs is necessary. Taurine bromamine (TauBr), the physiological product of hypobromous acid reaction with taurine, shows antioxidant, anti-inflammatory, and anti-bacterial properties. Importantly, P. acnes, a potential pathogenic agent for acne vulgaris, is extremely sensitive to TauBr. In addition, TauBr inhibits the generation of H(2)O(2) by activated neutrophils, which seems to be crucial for reducing the number and severity of inflammatory acne lesions. All these data strongly support the concept of using TauBr for topical anti-acne therapy. In our pilot clinical study, we have compared the efficacy of TauBr cream with clindamycin gel, one of the most common topical agents used in the treatment of acne. After 6 weeks, both treatments produced comparable, beneficial results. More than 90% of patients improved clinically with similar reductions in a number of acne lesions (approximately 65%). Therefore, the results from clinical studies are consistent with previous in vitro data and strongly suggest that TauBr could be considered a new therapeutic option in inflammatory acne.

Interleukin-6 (IL-6) and interleukin-8 (IL-8) are implicated in the pathogenesis of rheumatic diseases. In affected joints fibroblast-like synoviocytes (FLS) are the major source of these pro-inflammatory cytokines. We have previously found that production of both cytokines is inhibited in vitro by taurine chloramine (Tau-Cl). Heme oxygenase (HO-1) activity was also reported to restrict synthesis of various inflammatory mediators, including IL-6 and IL-8. The aim of present study was to investigate whether this enzyme activity is implicated in the mechanism of Tau-Cl suppressive effect. We have shown that in rheumatoid FLS both hemin (known HO-1 inducer) and Tau-Cl significantly up-regulate HO-1 expression at the mRNA and protein levels and simultaneously inhibit IL-1 beta-triggered production of pro-inflammatory cytokines. However, the inhibitory potency of these compounds differs, because hemin is more potent inhibitor of IL-8 than IL-6 production, while Tau-Cl exerts opposite effect. Importantly, pretreatment of the cells with HO-1 inhibitor completely reverses the inhibitory effect of hemin on both cytokines production. However, in Tau-Cl treated cells this inhibitor fully restores only IL-8 secretion but has weaker effect on IL-6 response. Thus, the present results: (i) support HO-1 activity to be relevant to negatively control production of pro-inflammatory cytokines, and (ii) underline implication of HO-1 in mediating Tau-Cl inhibitory action.

The aim of this study was to investigate and describe basic features of Pan_02 murine pancreatic ade- nocarcinoma tumor model. Pan_02 has very low sensitivity to chemotherapeutics therefore it is very similar to human pancreatic cancers.Mice were subcutaneously injected with different number of cells and tumor growth was measured. Tumors were also investigated with ultrasonograph VEVO2100 in doppler mode to detect viable and function- al blood vessels. Collected tumor samples were investigated to asses necrosis and blood vessel permeability.We found substantial differences in tumor growth depending on a number of inoculated tumor cells. Mice injected with 0.5 × 106 cells gave the most consistent pattern of growth. All tumors showed substantial vascularisation but bigger tumors were more likely to develop larger blood vessels instead of a more dense network.Murine Pan_02 cancer model shares many features with human PDAC cancers and therefore it is a good model to study new drugs. Injection of 0.5 × 106 cells gives consistent results although it requires more time for the tumor to grow. It also allows the immune system to adapt. Owing ta good vascularisation, Pan_02 is a good model to study chemotherapy against pancreatic adenocarcinoma but it may not be the best model for immunotherapy since it does not respond to the immune stimulation (unpublished data).