Mast cells as a target in the treatment of rheumatoid arthritis

— Mast cells represent a unique cell population, which is involved in a number of immune responses in our body. Mast cells (MCs) release an array of potent pro-inflammatory mediators and cytokines upon activation that are either pre-stored in the granules or synthesised de novo. These mediators can make a substantial contribution to the initiation and perpetuation of the inflammatory processes. This review provides an insight for the potential role of MCs in rheumatoid arthritis (RA). The data on mast cell distribution in the rheumatoid joint along with the information obtained from in vitro experiments and observations in animal models suggest that these cells may be involved in RA. The encouraging results of MC inactivating therapy in animal models of arthritis indicate that MC stabilizers may prove beneficial as a supplementary therapy in RA.     

Effects of orally available prodrug of cromoglycic acid on collagen-induced arthritis mice

Cromoglicate lisetil (CL) is an orally deliverable prodrug of cromoglycic acid, having diethyl promoieties and a lysyl promoiety for its optimum drug-delivery. We examined the effects of CL on bovine type II collagen (CII)-induced arthritis (CIA) of male DBA/1J mice, an experimental model for human rheumatoid arthritis, and its action mechanism. CL (100 mg/kg/day) was given by gavage to CII-immunized mice once daily for 6 weeks, starting when arthritic symptoms became evident. Symptomatic scores of arthritis obviously elevated in non-treated CIA mice at week 6.5 after initial immunization and continued elevated thereafter throughout the experiment, the elevation which was reduced by CL. CL also improved radiographic score of phalangeal destruction and pathohistological indexes at the end of treatment period. Serum anti-CII antibody titer was increased in non-treated CIA mice and the elevation was reduced by CL treatment. Mast cells (MCs) number in arthritic region was increased in non-treated CIA mice but not by CL treatment. In conclusion, oral CL treatment proved beneficial in CIA mice. Observed correlation between the CL effect on CIA and that on MCs number suggests the potential contribution of MCs to accelerate chronic arthritic processes and may further implicate potential action mechanism of CL, which may act by regulating MC functions for chronic inflammation.     

Mast cells and inflammatory heart disease: potential drug targets

Inflammation underlies the pathogenesis of many common cardiovascular diseases (CVD) such as myocardial infarction, atherosclerosis, myocarditis and dilated cardiomyopathy. Allergic disorders like allergic rhinitis and asthma, both chronic inflammatory conditions, have recently been linked to increased CVD and death. Studies have found that increased IgE levels, eosinophilia, positive skin-prick tests, self-reported asthma and enzymes that regulate leukotriene synthesis (5-lipoxygenase) predict a high risk for atherosclerosis, stroke and myocardial infarction. Mast cells (MCs), cells involved in the pathogenesis of allergy and asthma, are emerging as key players in the regulation of inflammation and fibrosis in the heart and vasculature. Our laboratory has found that MC numbers are increased in mice susceptible to developing chronic dilated cardiomyopathy. The fibrosis associated with chronic heart disease is increased by MC degranulation. MCs can also act as antigen-presenting cells increasing inflammation in the heart through Toll-like receptor-4 signaling and increased proinflammatory cytokine production. Similar inflammatory mechanisms are observed for myocarditis and atherosclerosis. Many of the drugs currently used to reduce heart disease act on mediators/ pathways downstream of MC degranulation. An improved understanding of the role of MCs in regulating inflammation and fibrosis will enable researchers and clinicians to better treat heart disease.     

Pharmacological treatment options for <Emphasis Type="Italic">mast cell activation disease</Emphasis>

Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches.     

Microcystin congener- and concentration-dependent induction of murine neuron apoptosis and neurite degeneration

Cyanobacterial microcystins (MCs) represent a toxin group with > 100 variants, requiring active uptake into cells via organic anion-transporting polypeptides, in order to irreversibly inhibit serine/threonine-specific protein phosphatases. MCs are a human health hazard with repeated occurrences of severe poisonings. In the well-known human MC intoxication in Caruaru, Brazil (1996), patients developed signs of acute neurotoxicity, e.g., deafness, tinnitus, and intermittent blindness, as well as subsequent hepatotoxicity. The latter data, in conjunction with some animal studies, suggest that MCs are potent neurotoxins. However, there is little data to date demonstrating MC neuron-specific toxicity. MC exposure-induced cytotoxicity, caspase activity, chromatin condensation, and microtubule-associated Tau protein hyperphosphorylation (epitopes serine199/202 and serine396) were determined. Neurite degeneration was analyzed with confocal microscopy and neurite length determined using image analysis. MC-induced apoptosis was significantly increased by MC-LF and MC-LW, however, only at high concentrations (≥ 3μM), whereas significant neurite degeneration was already observed at 0.5μM MC-LF. Moreover, sustained hyperphosphorylation of Tau was observed with all MC congeners. The concentration- and congener-dependent mechanisms observed suggest that low concentrations of MC-LF and MC-LW can induce subtle neurodegenerative effects, reminiscent of Alzheimer's disease type human tauopathies, and thus should be taken more seriously with regard to potential human health effects than the apical cytotoxicity (apoptosis or necrosis) demonstrated at high MC concentrations.     

Mast cell apoptosis induced by siramesine,a sigma-2 receptor agonist

Mast cells (MCs) are well known for their detrimental effects in the context of allergic disorders. Strategies that limit MC function can therefore have a therapeutic value. Previous studies have shown that siramesine, a sigma-2 receptor agonist originally developed as an anti-depressant, can induce cell death in transformed cells through a mechanism involving lysosomal destabilization. Since MCs are remarkably rich in lysosome-like secretory granules we reasoned that MCs might be sensitive to siramesine. Here we show that murine and human MCs are highly sensitive to siramesine. Cell death was accompanied by secretory granule permeabilization, as shown by reduced acridine orange staining and leakage of granule proteases into the cytosol. Wild type siramesine-treated MCs underwent cell death with typical signs of apoptosis but MCs lacking serglycin, a proteoglycan crucial for promoting the storage of proteases within MC secretory granules, died predominantly by necrosis. A dissection of the underlying mechanism suggested that the necrotic phenotype of serglycin^−/− cells was linked to defective Poly(ADP-ribose) polymerase-1 degradation. In vivo, siramesine treatment of mice caused a depletion of the MC populations of the peritoneum and skin. The present study shows for the first time that MCs are highly sensitive to apoptosis induced by siramesine and introduces the possibility of using siramesine as a therapeutic agent for treatment of MC-dependent disease.     

End-organ protection in patients with hypertension: focus on the role of angiotensin receptor blockers on renal function

The renin-angiotensin system (RAS) plays a key role in a number of pathophysiological mechanisms that are involved in the development and progression of cardiovascular and renal disease. For these reasons, pharmacological antagonism of this system, particularly the blockade of formation or the receptor antagonism of angiotensin II, has been demonstrated to be an effective and safe strategy to reduce the burden of cardiovascular disease. Among different drug classes, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have provided an excellent alternative to ACE inhibitors, representing a more selective and a better tolerated pharmacological approach to interfere with the RAS. Results derived from large, international, randomized clinical trials have consistently indicated that ARB-based therapeutic strategies may effectively provide cardiovascular and renal disease prevention and protection in different clinical conditions across the entire cardiovascular continuum. This article reviews the pathophysiological rationale of RAS involvement in the pathogenesis of renal diseases, focusing on the beneficial effects provided by ARBs in terms of renal protection.     

The antipsychotic drug pimozide inhibits IgE-mediated mast cell degranulation and migration

BackgroundMast cells (MCs) mediate a key role in allergic diseases. Detailed studies of how the neuroleptic drug pimozide affects MC activity are lacking. The aim of this study was to investigate pimozide inhibition of immunoglobulin E (IgE)-mediated MC activation and MC-mediated allergic responses.MethodMCs were stimulated with anti-dinitrophenyl (DNP) IgE antibodies and DNP-horse serum albumin (HSA) antigen (Ag), and anti-allergic pimozide effects were detected by measuring β-hexosaminidase levels. Morphological changes were observed histologically. In vivo pimozide effects were assessed in passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-sensitized active systemic anaphylaxis mouse (ASA) model experiments. Levels of phosphorylated (p-) SYK (spleen tyrosine kinase) and MAPKs (mitogen-activated protein kinases) were detected in western blots.ResultsWe found that pimozide inhibited MC degranulation, reduced MC release of β-hexosaminidase dose-dependently in activated RBL-2H3 (IC₅₀: 13.52 μM) and bone marrow derived MC (BMMC) (IC₅₀: 42.42 μM), and reduced MC morphological changes. The IgE/Ag-induced migration effect was suppressed by pimozide treatment dose-dependently. Pimozide down-regulated IgE/Ag-induced phosphorylation of SYK and MAPKs in activated MCs. Moreover, pimozide attenuated allergic reactions in PCA and ASA model mice, and decreased MC populations among splenic cells.ConclusionsThe antipsychotic drug pimozide can suppress IgE-mediated MC activation in vitro and in vivo and should be considered for repurposing to suppress MC-mediated diseases.     

Recognition sites for microbes and components of the immune system on human mast cells: relationship to CD antigens and implications for host defense

Traditionally, mast cells (MCs) have been considered to play an important role in allergic disorders and helminth infections. More recently, MCs have been implicated in a variety of different infectious diseases including life-threatening disorders caused by viruses and bacteria. Apart from recognition through specific IgE, MCs are considered to recognize such bacteria and viruses via specific cell surface binding sites. In addition, MCs interact with diverse components and cells of the immune system and thereby may facilitate the targeting and the elimination of invading microbes in the tissues. The current article provides an overview on MC antigens contributing to microbe recognition and targeting as an important element of natural host-defense.     

B cell-targeted therapy for rheumatoid arthritis: an update on the evidence

Rheumatoid arthritis (RA) is a human systemic autoimmune disease with a prevalence of about 1%. Although an important role for B cells has been demonstrated in animal models of autoimmune, inflammatory arthritis, the importance of B cells in RA has been controversial for decades. The development of therapies targeting B cells may help to resolve this debate. Rituximab, a mouse-human chimeric monoclonal antibody against the B cell-specific antigen CD20, was the first B cell-targeted therapy tested in double-blind, placebo-controlled trials for RA. On the basis of the data from three separate trials, addition of rituximab to methotrexate appears to reduce significantly the signs and symptoms of rheumatoid factor-seropositive RA, as assessed by American College of Rheumatology (ACR) 20, 50 and 70 response criteria, and to be relatively safe. Significant questions about rituximab therapy still need to be addressed, including whether or not treatment with rituximab reduces radiographic progression of joint damage, the safety and efficacy of repeated courses of rituximab, and the long-term effects of rituximab on the immune system. Preliminary data on treatment of RA with belimumab, a fully human monoclonal antibody against B lymphocyte stimulator (a growth and survival factor for B cells) is now available. In a double-blind, placebo-controlled, phase II trial, belimumab was well tolerated and had a significant beneficial effect on the ACR 20 response. Thus, therapies specifically targeting B cells do appear to be effective in the treatment of RA, providing direct evidence that B cells are important in the pathogenesis of RA.     

一氧化氮对急性胰腺炎影响的研究进展

急性胰腺炎(Acute pancreatitis,AP)是一种病情凶险,病死率高的临床常见急腹症。AP的发病机制是一个复杂的、多种因素参与的病理生理过程,目前明确的发病机制尚未完全阐明。近年来,大量研究表明一氧化氮(Nitric oxide,NO)在急性胰腺炎的发生发展中起重要的作用。本文就NO对AP的影响作一综述。     

Peptide and non-peptide bradykinin receptor antagonists: role in allergic airway disease

Kinins are proinflammatory peptides that mediate a variety of pathophysiological responses. These actions occur through stimulation of two pharmacologically distinct receptor subtypes B1 and B2. In both human and animal airways, the majority of kinin-induced effects including bronchoconstriction, increases in vascular permeability and mucus secretion and cholinergic and sensory nerve stimulation appear to be bradykinin B2-receptor mediated. Peptidic and non-peptidic receptor antagonists have been developed as potential therapeutic agents. These antagonists are effective in blocking kinin-induced effects in a variety of animal models and in some instances, have been used effectively in animal models of allergic airway disease to alleviate allergen-induced pathophysiological airway responses. This review summarizes relevant studies supporting the evidence that bradykinin B2 receptor antagonism and/or upstream inhibition of tissue kallikrein will be beneficial in the treatment of inflammatory airway diseases.     

Will treatment of rheumatoid arthritis with an IL-6R inhibitor help facilitate the ‘age of remission’?

Background: Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic disease, which negatively influences patients’ quality of life, work productivity and longevity. Current therapies include traditional and biologic disease-modifying antirheumatic drugs (DMARDs). Although these are effective for many, a substantial proportion of patients fail to respond to these agents, suffer from loss of efficacy and/or experience unpleasant side effects, highlighting the need for alternatives. Objectives/methods: To address how a greater proportion of RA patients may potentially achieve disease remission, we reviewed data on IL-6 as a therapeutic target. Results/conclusions: IL-6 is an important driver of RA pathogenesis, mediating both articular and systemic effects of the disease. Tocilizumab, an inhibitor of the IL-6 receptor (IL-6R), is beneficial in treating RA in a variety of clinical contexts. Evidence to date supports the use of tocilizumab, as monotherapy or combination therapy, as an effective approach to the treatment of RA. Here, we discuss key efficacy and safety data from the recently published Phase III trials.     

Rosmarinic acid from Perillae Herba produces an antidepressant-like effect in mice through cell proliferation in the hippocampus

Rosmarinic acid (RA) is one of major polyphenolic ingredients of Perillae Herba (a leaf of Perilla frutescens), and has an antidepressant-like property in animal models of depression. However, the mechanism(s) underlying this activity are unknown. Recent studies have reported that regulation of hippocampal neurogenesis is associated with the pathogenesis of depression. To elucidate the mode of action of RA-induced antidepressant-like activity, proliferative effect of RA on newborn cells in the dentate gyrus of mouse hippocampus was investigated using immunohistochemical analysis with bromodeoxyuridine (BrdU), a marker of proliferating cells. RA treatment for 7 or 14 d significantly increased in the number of BrdU-positive cells in inverse correlation with significant reductions in immobility in a forced swimming test, an animal model of depression, in a dose-dependent manner. However, locomotor activities were not affected. These results suggest that RA produces an antidepressant-like effect at least in part via the proliferation of newborn cells in the dentate gyrus of the hippocampus.     

Review of constructing animal models of depression after myocardial infarction北大核心CSCD

心肌梗死后抑郁(depression after myocardial infarction,DAMI)临床发病率较高,对患者的身心健康造成较大危害,但发病机制尚不清楚。采用能模拟人类DAMI发病原因和生物学反应的动物模型进行基础研究,是探索疾病机制的有效途径。该文将动物选择、模型选择、模型制备、行为学评价等建模过程中存在的问题进行总结和思考,以期为DAMI的模型研究提供参考。     

Oral toxicity of extracts of the microcystin-containing cyanobacterium Planktothrix agardhii to the medaka fish (Oryzias latipes)

As previously demonstrated the medaka fish appears to offer a good model for studies of microcystins (MCs) effects. Since cyanobacterial toxins are released with other molecules in the aquatic environment when the producers are dying, in this study, we performed additional experiments in order to compare the described effects obtained with the pure toxin microcystin-LR (MC-LR), among the most toxic MCs, to those induced by complex extracts of an MCs-producer Planktothrix agardhii, strain PMC 75.02 and a natural bloom containing the MCs-producer P. agardhii. The toxicity of these extracts containing several variants of MC was determined in adult medaka treated by gavage. Extracts of an MCs-free strain of P. agardhii (PMC 87.02) were assayed for comparison. Extracts effects were analysed on two tissues, liver and intestine by means of photon and transmission electron microscopy. MC was localized in these tissues by immunocytochemistry. No effect was detectable with extracts of the MCs-free P. agardhii strain. The two MCs-P. agardhii extracts (strain and natural bloom) were able to induce harmful effects in the liver and intestine of the medaka fish in acute intoxication by gavage. In these target organs as shown by toxin immunolocalization, reactions leading to cell disjunction and lysis were observed apparently associated with an immune reaction implying MC containing macrophages. These effects are similar to those previously described with photonic microscopy in medaka treated with pure MC-LR with additional results obtained under the electron microscope. Since no significant effect was detected with the MCs-free (PMC 87.02) extract, we then conclude that MCs, even in complex association with other cyanobacterial components, should be responsible for the toxic effects observed in treated fish.     

Animal models of central nervous system immune-mediated diseases: therapeutic interventions with bioactive peptides and mimetics

Experimental allergic encephalomyelitis (EAE) is a T helper 1 (Th1) mediated autoimmune disease and the principal animal model for multiple sclerosis (MS). Like MS, EAE is characterized by a coordinated inflammatory attack on the myelin sheath in the central nervous system (CNS), with damage to axons. No matter whether the ideal animal model is not yet available, much knowledge concerning the pathogenesis of MS has been achieved through studies on EAE. Dissecting the underlying immune mechanisms provided recognition of several myelin antigens that are vulnerable in autoimmune attack. The beneficial effect and the mechanism of action of a number of the currently used immunomodulating agents in MS therapy were first indicated in EAE. Altered peptide ligands (APL) can modulate T-cell responses to native peptide antigens implicated in the pathogenesis of autoimmune diseases such as MS and EAE. However, peptide therapy is hindered due to the sensitivity of peptides to proteolytic enzymes as well as due to some immune-mediated side effects. A number of cyclic myelin peptide analogs seem to be potential candidates in maintaining the biological function of the original peptide and effective in controlling inflammation in EAE. Additional data regarding the immunomodulating and neuroprotective effect of these much promising agents is required. Based on the data from studies on EAE models, clinical trials should also be designed in order to elucidate the impact of such APL-induced immune responses in MS disease activity. These clinical trials should carefully incorporate monitoring of both clinical, neuroimaging and immunological parameters.     

Suppression of lncRNA Snhg1 inhibits high glucose-induced inflammation and proliferation in mouse mesangial cells

Diabetic nephropathy (DN) is the direct cause of end-stage renal disease, and nephritic inflammation plays a role in its growth and advancement. Aberrant expression of long non-coding RNAs (lncRNAs) correlates with many diseases, including DN. In this study, we investigated whether lncRNA small nucleolar RNA host gene 1 (Snhg1) was mechanistically involved in inflammation and mesangial cell (MC) proliferation in DN. We found that Snhg1 was significantly upregulated in DN renal tissues and high glucose (HG)-treated MCs. Overexpression of Snhg1 promoted inflammatory cytokine expression in MCs and MC proliferation under low-glucose conditions; meanwhile, Snhg1 knockdown suppressed inflammatory cytokine production and MC proliferation under HG conditions. Mechanistically, Snhg1 was found to directly bind miR-27b, thereby preventing the miRNA from binding its target KDM6B mRNA. Furthermore, miR-27b overexpression recapitulated the inhibitory effects of Snhg1 knockdown, whereas restoration of Snhg1 expression attenuated the function of miR-27b in MCs under HG conditions. Taken together, these results indicate that suppression of Snhg1 inhibited HG-induced inflammation and proliferation of MCs by regulating the miR-27b/KDM6B axis.     

A forskolin derivative, colforsin daropate hydrochloride, inhibits rat mesangial cell mitogenesis via the cyclic AMP pathway

A forskolin derivative, colforsin daropate hydrochloride (CDH), has been introduced as an inotropic agent that acts directly on adenylate cyclase to increase intracellular cyclic AMP (cAMP) levels and ventricular contractility, resulting in positive inotropic activity. We investigated the effects of CDH on rat mesangial cell (MC) proliferation. CDH (10(-7)-10(-5) mol/l) inhibited [(3)H]thymidine incorporation into cultured rat MCs in a concentration-dependent manner. CDH (10(-7)-10(-5) mol/l) also decreased cell numbers in a similar manner, and stimulated cAMP accumulation in MCs in a concentration-dependent manner. A protein kinase A inhibitor, H-89, abolished the inhibitory effects of CDH on MC mitogenesis. These findings suggest that CDH would inhibit the proliferation of rat MCs via the cAMP pathway.     

Chemokines and atherosclerosis: focus on the CX3CL1/CX3CR1 pathway

Atherosclerosis is currently considered an inflammatory disease. Much attention has been focused on the potential role of inflammatory mediators as prognostic/diagnostic markers or therapeutic targets of atherosclerotic cardiovascular disease. CX3CL1 (or fractalkine) is a structurally and functionally unique chemokine with a well documented role in atherosclerosis. In its membrane bound form it promotes the firm adhesion of rolling leucocytes onto the vessel wall, while in its soluble form it serves as a potent chemoattractant for CX3CR1-expressing cells. Additionally, CX3CL1 exerts cytotoxic effects on the endothelium as well as anti-apoptotic and proliferative effects on vascular cells, affecting the context and stability of the atherosclerotic plaque. Studies on animal models have shown that the blockade of the CX3CL1/CX3CR1 pathway ameliorates the severity of atherosclerosis, while genetic epidemiology has confirmed that a genetically-defined less active CX3CL1/CX3CR1 pathway is associated with a reduced risk of atherosclerotic disease in humans. Although several studies support an important pathogenic role of CX3CL1/CX3CR1 in atherogenesis and plaque destabilization, this does not necessarily suggest that this pathway is a suitable therapeutic target or that CX3CL1 can serve as a prognostic/diagnostic biomarker. Further studies on the CX3CL1/CX3CR1 chemokine pathway are clearly warranted to justify the clinical relevance of its role in atherosclerosis.