Carbon monoxide regulates glycolysis-dependent NLRP3 inflammasome activation in macrophages.

Low dose of carbon monoxide (CO) has anti-inflammatory role through various signaling pathways. Cellular metabolism has been implicated in the activation of inflammation in immune cells. However, the mechanisms by which CO-dependent metabolic regulation affect the immune response remain unclear. Here we show that CO-dependent metabolic pathway regulates the activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome. CO-releasing molecule-3 (CORM-3) resulted in reduced glycolysis-dependent NLRP3 inflammasome activation in macrophages. The reduced mTORC1 activation by CORM-3 resulted in less glycolysis during NLRP3 inflammasome activation. CORM-3 suppressed caspase-1 activation and the secretion of interleukin (IL)-1ß and IL-18 in macrophages in response to lipopolysaccharide (LPS) and ATP. Moreover, CORM-3 inhibits the oligomerization of the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which is required for NLRP3-dependent caspase-1 activation. Furthermore, CORM-3-treated mice showed substantial reduction in IL-1ß production by hyperglycemia in a mouse model of streptozotocin (STZ)-induced diabetes. Our results suggest that CO regulates glycolysis-dependent NLRP3 inflammasome activation and may provide a therapeutic approach for inflammation in metabolic diseases.

Allergens, air pollutants, and childhood allergic diseases.

BACKGROUND: The synergistic effect of allergens and air pollutants on the risk of allergic diseases is unclear. OBJECTIVE: To evaluate the joint effect of outdoor pollutants and indoor allergens on the risk of allergic diseases. METHODS: We enrolled 2661 kindergarten children from the CEAS cohort. Data on allergic diseases and environmental exposure were collected. Skin prick tests were performed. Individual exposure to air pollution was estimated using a geographic information system with the mean concentration of air pollutants. Multiple logistic regression analysis was performed to estimate the association between air pollutants, allergen exposure and the risk of allergic diseases with adjustments for potential confounders. RESULTS: Overall, 12.6% of the children had asthma, 30.0% had allergic rhinitis (AR), and 14.4% had atopic dermatitis (AD). Mite sensitization significantly increased the risk of AD, AR, and asthma (OR (95%CI) 2.15 (1.53-3.03), 1.94 (1.46-2.58), and 2.31 (1.63-3.29), respectively). Exposure to PM10, PM(2.5), CO, and O(3) was associated with asthma (OR (95% CI) 1.39 (1.03-1.87), 1.45 (1.07-1.97), 1.36 (1.01-1.83), and 0.68 (0.51-0.92), respectively). PM(2.5) may have increased the risk of AR (OR (95% CI) 1.54 (1.03-2.32). Mite sensitization showed a synergistic effect with PM(2.5) on the development of asthma (p < 0.001). Moreover, mite allergens may modify the effect of air pollutants on allergic diseases. CONCLUSION: Dust mites and PM(2.5) play an important role on the risk of asthma and AR. Exposure to PM(2.5) and mite allergens had a synergistic effect on the development of asthma. Avoiding co-exposure to allergens and air pollutants is important.

A Systematic Review of Innate Immunomodulatory Effects of Household Air Pollution Secondary to the Burning of Biomass Fuels.

BACKGROUND: Household air pollution (HAP)-associated acute lower respiratory infections cause 455,000 deaths and a loss of 39.1 million disability-adjusted life years annually. The immunomodulatory mechanisms of HAP are poorly understood. OBJECTIVES: The aim of this study was to conduct a systematic review of all studies examining the mechanisms underlying the relationship between HAP secondary to solid fuel exposure and acute lower respiratory tract infection to evaluate current available evidence, identify gaps in knowledge, and propose future research priorities. METHODS: We conducted and report on studies in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. In all, 133 articles were fully reviewed and main characteristics were detailed, namely study design and outcome, including in vivo versus in vitro and pollutants analyzed. Thirty-six studies were included in a nonexhaustive review of the innate immune system effects of ambient air pollution, traffic-related air pollution, or wood smoke exposure of developed country origin. Seventeen studies investigated the effects of HAP-associated solid fuel (biomass or coal smoke) exposure on airway inflammation and innate immune system function. RESULTS: Particulate matter may modulate the innate immune system and increase susceptibility to infection through a) alveolar macrophage-driven inflammation, recruitment of neutrophils, and disruption of barrier defenses; b) alterations in alveolar macrophage phagocytosis and intracellular killing; and c) increased susceptibility to infection via upregulation of receptors involved in pathogen invasion. CONCLUSIONS: HAP secondary to the burning of biomass fuels alters innate immunity, predisposing children to acute lower respiratory tract infections. Data from biomass exposure in developing countries are scarce. Further study is needed to define the inflammatory response, alterations in phagocytic function, and upregulation of receptors important in bacterial and viral binding. These studies have important public health implications and may lead to the design of interventions to improve the health of billions of people daily.

The therapeutic potential of carbon monoxide for inflammatory bowel disease.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory disorders of the intestinal tract. Because the precise pathogenesis of IBD remains unclear, it is important to investigate the pathogenesis of IBD and to evaluate new anti-inflammatory strategies. Recent accumulating evidence has suggested that carbon monoxide (CO) may act as an endogenous defensive gaseous molecule to reduce inflammation and tissue injury in various organ injury models, including intestinal inflammation. Furthermore, exogenous CO administration at low concentrations is protective against intestinal inflammation. These data suggest that CO may be a novel therapeutic molecule in patients with IBD. In this review, we present what is currently known regarding the therapeutic potential of CO in intestinal inflammation.

Protective role of hemeoxygenase-1 in gastrointestinal diseases.

Disorders and diseases of the gastrointestinal system encompass a wide array of pathogenic mechanisms as a result of genetic, infectious, neoplastic, and inflammatory conditions. Inflammatory diseases in general are rising in incidence and are emerging clinical problems in gastroenterology and hepatology. Hemeoxygenase-1 (HO-1) is a stress-inducible enzyme that has been shown to confer protection in various organ-system models. Its downstream effectors, carbon monoxide and biliverdin have also been shown to offer these beneficial effects. Many studies suggest that induction of HO-1 expression in gastrointestinal tissues and cells plays a critical role in cytoprotection and resolving inflammation as well as tissue injury. In this review, we examine the protective role of HO-1 and its downstream effectors in modulating inflammatory diseases of the upper (esophagus and stomach) and lower (small and large intestine) gastrointestinal tract, the liver, and the pancreas. Cytoprotective, anti-inflammatory, anti-proliferative, antioxidant, and anti-apoptotic activities of HO-1 make it a promising if not ideal therapeutic target for inflammatory diseases of the gastrointestinal system.

Heme oxygenase and carbon monoxide as an immunotherapeutic approach in transplantation and cancer.

Heme oxygenases (HOs) are the rate-limiting intracellular enzymes that degrade heme into carbon monoxide (CO), biliverdin and free divalent iron. Among HOs, HO-1 is the only isoform that is highly inducible in response to numerous stress factors and proinflammatory cytokines. This enzyme has shown cytoprotective, antioxidant and anti-inflammatory properties. Moreover, HO-1 and, in particular, CO also have tolerogenic actions in adaptive immune responses. HO-1 can provide immunosuppression through its expression by regulatory T cells or antigen-presenting cells. The physiological importance of HO-1 has been demonstrated in both mice and humans, and modulation of HO-1 expression has therapeutic effects in a variety of disorders involving inflammation and immune responses, including organ transplantation and cancer. Consistently, upregulation of the HO-1 pathway has a significant protective effect against spontaneous or induced autoimmune diseases, allergy and can be beneficial to graft survival. However, HO-1 may also play a role in tumorigenesis by lowering antitumor innate immune responses that control tumor growth or reduce tumor expansion. Thus, controlling HO-1 expression may be of great interest in immune intervention protocols where tolerance is desirable, such as in transplantation, or where enhanced immunogenicity is needed in the case of cancer.

CO-opting the host HO-1 pathway in tuberculosis and malaria.

Infection with Mycobacterium tuberculosis and Plasmodium species results in upregulation of the host heme oxygenase-1 pathway. In tuberculosis infection, this leads to upregulation of the bacterial "dormancy regulon," whereas in malaria, it enhances the efficiency with which sporozoites develop into exoerythrocytic stages. Here we discuss these findings as well as some of the interesting questions they raise.

Mycobacterium tuberculosis senses host-derived carbon monoxide during macrophage infection.

Mycobacterium tuberculosis (MTB) expresses a set of genes known as the dormancy regulon in vivo. These genes are expressed in vitro in response to nitric oxide (NO) or hypoxia, conditions used to model MTB persistence in latent infection. Although NO, a macrophage product that inhibits respiration, and hypoxia are likely triggers in vivo, additional cues could activate the dormancy regulon during infection. Here, we show that MTB infection stimulates expression of heme oxygenase (HO-1) by macrophages and that the gaseous product of this enzyme, carbon monoxide (CO), activates expression of the dormancy regulon. Deletion of macrophage HO-1 reduced expression of the dormancy regulon. Furthermore, we show that the MTB DosS/DosT/DosR two-component sensory relay system is required for the response to CO. Together, these findings demonstrate that MTB senses CO during macrophage infection. CO may represent a general cue used by pathogens to sense and adapt to the host environment.

Carbon monoxide orchestrates a protective response through PPARgamma.

Carbon monoxide (CO) suppresses proinflammatory responses in macrophages reacting to LPS. We hypothesize that CO acts by inducing a molecule(s) that suppresses the inflammatory response to subsequent stress. Exposure of macrophages to CO alone in vitro produced a brief burst of mitochondrial-derived ROS, which led to expression of PPARgamma. PPARgamma expression proved essential for mediating the anti-inflammatory effects of CO. Blocking the CO-mediated increase in ROS generation prevented PPARgamma induction, and blocking PPARgamma prevented CO's anti-inflammatory effects. In a model of acute lung injury in mice, CO blocked expression of Egr-1, a central mediator of inflammation, and decreased tissue damage; inhibition of PPARgamma abrogated both effects. These data identify the mitochondrial oxidases as an (perhaps the) initial cellular target of CO and demonstrate that CO upregulates expression of PPARgamma via the mitochondria, which assures that a subsequent stress stimulus will lead to a cytoprotective as opposed to a proinflammatory phenotype.

Heme oxygenase-1: unleashing the protective properties of heme.

Heme oxygenase (HO)-1 catabolizes heme into three products: carbon monoxide (CO), biliverdin (which is rapidly converted to bilirubin) and free iron (which leads to the induction of ferritin, an iron-binding protein). HO-1 serves as a "protective" gene by virtue of the anti-inflammatory, anti-apoptotic and anti-proliferative actions of one or more of these three products. Administration of CO, biliverdin, bilirubin or iron-binding compounds is protective in rodent disease models of ischemia-reperfusion injury, allograft and xenograft survival, intimal hyperplasia following balloon injury or as seen in chronic graft rejection and others. We suggest that the products of HO-1 action could be valuable therapeutic agents and speculate that HO-1 functions as a "therapeutic funnel", mediating the beneficial effects attributed to other molecules, such as interleukin-10 (IL-10), inducible nitric oxide synthase (NOS2; iNOS) and prostaglandins. This Review is the third in a series on the regulation of the immune system by metabolic pathways.

Assessment of contact allergen cross-reactivity by retesting.

At former allergic contact dermatitis reaction sites retesting causes augmented hyper-reactivity, characterized by an accelerated onset within a few hours. This expression of 'local skin memory' has been ascribed to locally persisting allergen-specific effector/memory T cells. To verify this hypothesis, we investigated whether accelerated retest reactivity also occurs with cross-reactive allergens. Guinea pigs were immunized with either or both 2,4-dinitrochlorobenzene (DNCB) and 2-hydroxyethyl methacrylate (HEMA), and primary skin tests to these and cross-reactive methacrylic compounds were performed 12-21 days later. Subsequently, new skin tests were conducted 3 weeks later both at the former test ('retest') and contralateral, non-pretreated test ('control') sites, and skin test readings started 2 h later. Retest reactivity was evaluated by comparing retest and contralateral control reactions. Both contact sensitizers, HEMA and DNCB, induced strong retest reactivity, peaking at 4-6 h. Fully allergen-specific retest reactivity was observed when primary skin tests had been postponed until 21 days after immunization, most probably reflecting loss of accumulation of irrelevant allergen-primed T cells at that time. As hypothesized, retesting with various methacrylate congeners at primary HEMA, but not DNCB, skin test sites showed early hyperreactivity strengths in line with those observed earlier in conventional cross-reactivity studies. These results, therefore, support the view that local skin memory exhibits allergen specificity through residual allergen-primed T cells. Because the retesting procedure is readily applicable in clinical practice, it provides a tool not only for confirmation of doubtful contact allergic skin reactions, but also for distinguishing between true cross-reactivity and coincident multiple sensitization in man.

Carbon monoxide-dependent signaling.

It has become accepted that nitric oxide serves important functions in biological systems as a second messenger. Another diatomic gaseous molecule, carbon monoxide (CO), is also rapidly gaining acceptance as a signaling agent. Some of the activities of CO are analogous to those of nitric oxide in the vascular system and the brain, but CO also behaves in novel ways. Like nitric oxide, CO is capable of activating soluble guanylyl cyclase. This mechanism of CO signaling is important in vasodilation and neurotransmission. There is growing evidence, however, that CO also acts independently of soluble guanylyl cyclase. CO has been shown to protect against septic shock and lung injury in animal models, and the mitogen-activated protein kinase system appears to mediate this cytoprotective effect. Although much remains to be elucidated about the mechanisms of cell signaling by CO, the pace of discovery in this field is making the picture clearer with every passing day.

Modulation of the immunological response of guinea pig mast cells by carbon monoxide.

Challenge of guinea pig mast cells with antigen under aerobic conditions induced the expected release of histamine and led to a significant increase in intracellular calcium ([Ca2+]i) and cyclic adenosine monophosphate (cAMP) levels. Prior exposure to CO decreased the immunological histamine release. This effect was accompanied by a decrease in the levels of [Ca2+]i and by an increase in the cyclic guanosine monophosphate (cGMP) levels. The exposure of mast cells to nitrogen (N2) did not modify the release of histamine. The CO-mediated inhibition of the immunological release of histamine was reversed by the soluble guanylate cyclase inhibitor (1 H-[1.2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) and by oxyhaemoglobin (HbO2). Incubation of mast cells for 4 h with hemin, a heme oxygenase (HO) inducer, resulted in an increase in HO activity, measured as bilirubin production. Hemin abated the immunological release of histamine, in similar fashion to exogenous CO, and increased the cGMP levels. These effects were reversed by ODQ and HbO2. It is proposed that CO from an exogenous or endogenous source stimulates guanylyl cyclase and causes cGMP formation which then induces calcium to be sequestrated so that the [Ca2+]i concentration falls and histamine release is inhibited.

Recurrent diffuse pulmonary hemorrhage with minor kidney lesions.

This case report concerns a 14-year-old boy with a 3 month history of dyspnea and iron deficiency anemia. On admission he had hemoptysis and bilateral pulmonary shadows. Transbronchial lung biopsies showed linear deposits of IgG and C3 in the alveolar basement membrane, but no anti-GBM antibodies were observed in serum or kidney biopsy. The ratio of the T cell subpopulations T4/T8 in peripheral blood was in the early stage, 5 and, thus, elevated. The patient was given prednisolone 1 to 0.25 mg/kg and cyclophosphamide 2 mg/kg with temporary cessation of pulmonary bleeding. Hemoptysis recurred and plasma exchange was performed with success.