Bushfire smoke is pro-inflammatory and suppresses macrophage phagocytic function.
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ABSTRACT:
SUBMITTER: Hamon R
PROVIDER: S-EPMC6128914 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Published data for the Streptococcus pneumoniae virulence factor Pneumolysin (Ply) show contradictory effects on the host inflammatory response to infection. Ply has been shown to activate the inflammasome, but also can bind to MRC-1 resulting in suppression of dendritic cell inflammatory responses. We have used an in vitro infection model of human monocyte-derived macrophages (MDM), and a mouse model of pneumonia to clarify whether pro- or anti-inflammatory effects dominate the effects of Ply on the initial macrophage inflammatory response to S. pneumoniae, and the consequences during early lung infection. We found that infection with S. pneumoniae expressing Ply suppressed tumour necrosis factor (TNF) and interleukin-6 production by MDMs compared to cells infected with ply-deficient S. pneumoniae. This effect was independent of bacterial effects on cell death. Transcriptional analysis demonstrated S. pneumoniae expressing Ply caused a qualitatively similar but quantitatively lower MDM transcriptional response to S. pneumoniae compared to ply-deficient S. pneumoniae, with reduced expression of TNF and type I IFN inducible genes. Reduction of the MDM inflammatory response was prevented by inhibition of SOCS1. In the early lung infection mouse model, the TNF response to ply-deficient S. pneumoniae was enhanced and bacterial clearance increased compared to infection with wild-type S. pneumoniae. Overall, these data show Ply inhibits the initial macrophage inflammatory response to S. pneumoniae, probably mediated through SOCS1, and this was associated with improved immune evasion during early lung infection.
| S-EPMC10497322 | biostudies-literature
Project description:IntroductionExposure to ambient air pollution is strongly associated with increased cerebrovascular diseases. The 2019-20 bushfire season in Australia burnt 5.4 million hectares of land in New South Wales alone, with smoke so severe it affected cities in Argentina, 11,000 km away. The smoke emitted by bushfires consists of both gaseous and particle components. It is important to note that exposure to particulate matter has been shown to be linked to a heightened risk of stroke, which is the primary kind of cerebrovascular illness, as well as an increased likelihood of hospitalisations and mortality. However, the available data is inadequate in terms of documenting the response of patients diagnosed with a proven cerebrovascular illness to bushfire smoke. Additionally, there is a lack of information about the health effects associated with particulate matter throughout the bushfire season and on days when smoke was present in 2019 and 2020.Therefore, we aimed to determine the effects of (i) short-term air pollution triggered by bushfires and (ii) high smoke days in increasing the daily number of hospital admissions with cerebrovascular diseases.Materials and methodsHospitalisation data were accessed from the admitted patient dataset from seven local Government areas of Hunter New England Local Health District. The bushfire period was defined from 1 October 2019 to 10 February 2020, and a same period from 2018-19 as the control. High bushfire smoke days were days when the average daily concentration of particulate matter was higher than the 95th percentile of the control period. Poisson regression models and fixed effect meta-analysis were used to analyse the data.ResultsIn total, 275 patients with cerebrovascular admissions were identified, with 147 (53.5%) during the bushfire (2019-20) and 128 (46.5%) in the control period (2018-19). There was no significant increase in daily admissions for cerebrovascular disease (Incidence Rate Ratio, IRR: 1.04; 95% CI: 0.81-1.34; p-value: 0.73), acute stroke (IRR: 1.15; 95% CI: 0.88-1.50; p-value: 0.29) or acute ischaemic stroke (IRR: 1.18; 95% CI: 0.87-1.59; p-value: 0.28), over the entire bushfire period. However, the high bushfire smoke days were associated with increased acute ischaemic stroke-related hospital admissions across lead 0-3 and the highest cumulative effect was observed with lead 0 (IRR:1.52; 95% CI: 1.01-2.29; p-value: 0.04). In addition, during the bushfire period, particulate matter, both PM10 and PM2.5 (defined as particulates that have an effective aerodynamic diameter of 10, and 2.5 microns, respectively), were also associated with increased acute ischaemic stroke admissions with a lag of 0-3 days.Discussion and conclusionThe results suggested a possible association between particulate matter and high smoke days with increased hospital admissions due to acute ischaemic stroke during the recent Australian bushfire season.
| S-EPMC11318436 | biostudies-literature
Project description:GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely pro-inflammatory, which can augment inflammatory response, and GPR84 also functions as a pro-phagocytic receptor to enhance phagocytic activities of macrophages. In this study, we show that the activation of GPR84 by the synthetic agonist 6-OAU can synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. We also determine a high-resolution structure of the GPR84-Gi signaling complex with 6-OAU. This structure reveals an occluded binding pocket for 6-OAU, the molecular basis of receptor activation involving non-conserved structural motifs of GPR84, and an unusual Gi-coupling interface. Together with computational docking and simulations studies, this structure also suggests a mechanism for the high selectivity of GPR84 for MCFAs and a potential routes of ligand binding and dissociation. These results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.
| S-EPMC10502086 | biostudies-literature
Project description:GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely pro-inflammatory, which can augment inflammatory response, and GPR84 also functions as a pro-phagocytic receptor to enhance the phagocytic activities of macrophages. In this study, we first showed that the activation of GPR84 by the synthetic agonist 6-OAU could synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. Then, we determined a high-resolution structure of the GPR84-Gi signaling complex with 6-OAU. This structure revealed a completely occluded binding pocket for 6-OAU, the molecular basis of receptor activation involving non-conserved structural motifs of GPR84, and an unusual Gi-coupling interface. Together with computational docking and simulations studies, our structure also suggested the mechanism for the high selectivity of GPR84 for MCFAs and the potential routes of ligand binding and dissociation. Our results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.
| S-EPMC9949259 | biostudies-literature
Project description:Remyelination can occur naturally in demyelinating lesions, but often fails in human demyelinating diseases such as multiple sclerosis (MS). The function of the innate immune system is essential for the regenerative response, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory nuclear factor κB (NF-κB) dependent activation occurs in phagocytes rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88), the canonical adaptor for inflammatory signaling pathways downstream of toll-like receptors (TLRs). MyD88-deficient mice and zebrafish were impaired not only in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of tumor necrosis factor-α (TNF-α) in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is an evolutionary conserved mechanism necessary for degrading myelin debris, essential for inflammation resolution, and for initiating the secretion of pro-inflammatory myelin repair molecules.
2020-02-17 | PXD014625 | Pride
Project description:BackgroundAlpha-1 antitrypsin deficiency (AATD) is a genetic disorder most commonly secondary to a single mutation in the SERPINA1 gene (PI*Z) that causes misfolding and accumulation of alpha-1 antitrypsin (AAT) in hepatocytes and mononuclear phagocytes which reduces plasma AAT and creates a toxic gain of function. This toxic gain of function promotes a pro-inflammatory phenotype in macrophages that contributes to lung inflammation and early-onset COPD, especially in individuals who smoke cigarettes. The aim of this study is to determine the role of cigarette exposed AATD macrophages and bronchial epithelial cells in AATD-mediated lung inflammation.MethodsPeripheral blood mononuclear cells from AATD and healthy individuals were differentiated into alveolar-like macrophages and exposed to air or cigarette smoke while in culture. Macrophage endoplasmic reticulum stress was quantified and secreted cytokines were measured using qPCR and cytokine ELISAs. To determine whether there is "cross talk" between epithelial cells and macrophages, macrophages were exposed to extracellular vesicles released by airway epithelial cells exposed to cigarette smoke and their inflammatory response was determined.ResultsAATD macrophages spontaneously produce several-fold more pro-inflammatory cytokines as compared to normal macrophages. AATD macrophages have an enhanced inflammatory response when exposed to cigarette smoke-induced extracellular vesicles (EVs) released from airway epithelial cells. Cigarette smoke-induced EVs induce expression of GM-CSF and IL-8 in AATD macrophages but have no effect on normal macrophages. Release of AAT polymers, potent neutrophil chemo attractants, were also increased from AATD macrophages after exposure to cigarette smoke-induced EVs.ConclusionsThe expression of mutated AAT confers an inflammatory phenotype in AATD macrophages which disposes them to an exaggerated inflammatory response to cigarette smoke-induced EVs, and thus could contribute to progressive lung inflammation and damage in AATD individuals.
| S-EPMC9446525 | biostudies-literature
Project description:IntroductionMelioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a disease endemic in many tropical countries globally. Clinical presentation is highly variable, ranging from asymptomatic to fatal septicemia, and thus the outcome of infection can depend on the host immune responses. The aims of this study were to firstly, characterize the macrophage immune response to B. pseudomallei and secondly, to determine whether the immune response was modified in the presence of novel inhibitors targeting the virulence factor, the macrophage infectivity potentiator (Mip) protein. We hypothesized that inhibition of Mip in B. pseudomallei would disarm the bacteria and result in a host beneficial immune response.MethodsMurine macrophage J774A.1 cells were infected with B. pseudomallei K96243 in the presence of small-molecule inhibitors targeting the Mip protein. RNA-sequencing was performed on infected cells four hours post-infection. Secreted cytokines and lactose dehydrogenase were measured in cell culture supernatants 24 hours post-infection. Viable, intracellular B. pseudomallei in macrophages were also enumerated 24 hours post-infection.ResultsGlobal transcriptional profiling of macrophages infected with B. pseudomallei by RNA-seq demonstrated upregulation of immune-associated genes, in particular a significant enrichment of genes in the TNF signaling pathway. Treatment of B. pseudomallei-infected macrophages with the Mip inhibitor, AN_CH_37 resulted in a 5.3-fold reduction of il1b when compared to cells treated with DMSO, which the inhibitors were solubilized in. A statistically significant reduction in IL-1β levels in culture supernatants was seen 24 hours post-infection with AN_CH_37, as well as other pro-inflammatory cytokines, namely IL-6 and TNF-α. Treatment with AN_CH_37 also reduced the survival of B. pseudomallei in macrophages after 24 hours which was accompanied by a significant reduction in B. pseudomallei-induced cytotoxicity as determined by lactate dehydrogenase release.DiscussionThese data highlight the potential to utilize Mip inhibitors in reducing potentially harmful pro-inflammatory responses resulting from B. pseudomallei infection in macrophages. This could be of significance since overstimulation of pro-inflammatory responses can result in immunopathology, tissue damage and septic shock.
| S-EPMC10999550 | biostudies-literature
Project description:Macrophages are strategically distributed in mammalian tissues and play an essential role in priming immune response. However, macrophages need to constantly strike a balance between activation and inhibition state to avoid a futile inflammatory reaction. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage pro-inflammatory activation. Gain- and loss-of-function studies revealed that CITED2 is required for optimal peroxisome proliferator-activated receptor gamma (PPAR?) activation and attendant select anti-inflammatory gene expression in macrophages. More importantly, deficiency of CITED2 resulted in significant attenuation in rosiglitazone-induced PPAR? activity, PPAR? recruitment to target gene promoters and anti-inflammatory target gene expression in macrophages. Interestingly, deficiency of Cited2 strikingly heightened pro-inflammatory gene expression through stabilization of hypoxia-inducible factor 1 alpha (HIF1?) protein in macrophages. Further, overexpression of Egln3 or inhibition of HIF1? in Cited2-deficient macrophages completely reversed elevated pro-inflammatory cytokine/chemokine gene expression. Importantly, mice bearing a myeloid-specific deletion of Cited2 were highly susceptible to endotoxin-induced sepsis symptomatology and mortality. Collectively, our observations identify CITED2 as a novel negative regulator of macrophage pro-inflammatory activation and protect the host from inflammatory insults.
| S-EPMC5809687 | biostudies-other
Project description:Glycation and the accumulation of advanced glycation end products (AGEs) are known to occur during normal aging but also in the progression of several diseases, such as diabetes. Diabetes type II and aging both lead to impaired wound healing. It has been demonstrated that macrophages play an important role in impaired wound healing, however, the underlying causes remain unknown. Elevated blood glucose levels as well as elevated methylglyoxal (MGO) levels in diabetic patients result in glycation and increase of AGEs. We used MGO to investigate the influence of glycation and AGEs on macrophages. We could show that glycation, but not treatment with AGE-modified serum proteins, increased expression of pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-8 but also affected IL-10 and TNF-α expression, resulting in increased inflammation. At the same time, glycation reduced phagocytic efficiency and led to impaired clearance rates of invading microbes and cellular debris. Our data suggest that glycation contributes to changes of macrophage activity and cytokine expression and therefore could support the understanding of disturbed wound healing during aging and diabetes.
| S-EPMC6682540 | biostudies-literature
Project description:Necrotizing soft tissue infections are lethal polymicrobial infections. Two key microbes that cause necrotizing soft tissue infections are Streptococcus pyogenes and Clostridium perfringens. These pathogens evade innate immunity using multiple virulence factors, including cholesterol-dependent cytolysins (CDCs). CDCs are resisted by mammalian cells through the sequestration and shedding of pores during intrinsic membrane repair. One hypothesis is that vesicle shedding promotes immune evasion by concomitantly eliminating key signaling proteins present in cholesterol-rich microdomains. To test this hypothesis, murine macrophages were challenged with sublytic CDC doses. CDCs suppressed LPS or IFNγ-stimulated TNFα production and CD69 and CD86 surface expression. This suppression was cell intrinsic. Two membrane repair pathways, patch repair and intrinsic repair, might mediate TNFα suppression. However, patch repair did not correlate with TNFα suppression. Intrinsic repair partially contributed to macrophage dysfunction because TLR4 and the IFNγR were partially shed following CDC challenge. Intrinsic repair was not sufficient for suppression, because pore formation was also required. These findings suggest that even when CDCs fail to kill cells, they may impair innate immune signaling responses dependent on cholesterol-rich microdomains. This is one potential mechanism to explain the lethality of S. pyogenes and C. perfringens during necrotizing soft tissue infections.
| S-EPMC5915385 | biostudies-literature