LC3-Associated Phagocytosis and Inflammation Heckmann, Bradlee L.; Boada-Romero, Emilio; Cunha, Larissa D. ...
Journal of molecular biology,
11/2017, Letnik:
429, Številka:
23
Journal Article
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LC3-associated phagocytosis (LAP) is a novel form of non-canonical autophagy where LC3 (microtubule-associated protein 1A/1B–light chain 3) is conjugated to phagosome membranes using a portion of the ...canonical autophagy machinery. The impact of LAP to immune regulation is best characterized in professional phagocytes, in particular macrophages, where LAP has instrumental roles in the clearance of extracellular particles including apoptotic cells and pathogens. Binding of dead cells via receptors present on the macrophage surface results in the translocation of the autophagy machinery to the phagosome and ultimately LC3 conjugation. These events promote a rapid form of phagocytosis that produces an “immunologically silent” clearance of the apoptotic cells. Consequences of LAP deficiency include a decreased capacity to clear dying cells and the establishment of a lupus-like autoimmune disease in mice. The ability of LAP to attenuate autoimmunity likely occurs through the dampening of pro-inflammatory signals upon engulfment of dying cells and prevention of autoantigen presentation to other immune cells. However, it remains unclear how LAP shapes both the activation and outcome of the immune response at the molecular level. Herein, we provide a detailed review of LAP and its known roles in the immune response and provide further speculation on the putative mechanisms by which LAP may regulate immune function, perhaps through the metabolic reprogramming and polarization of macrophages.
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•Comprehensive overview of LC3-associated phagocytosis (LAP).•LAP bridges the phagocytic and autophagic pathways.•Signaling to LAP and regulation of LAP activation by the canonical autophagy machinery.•LAP quenches inflammation and shapes the immune response towards anti-inflammation.•LAP promotes the immunosilent clearance of dying cells and prevents autoimmunity.
Targeting autophagy in cancer cells and in the tumor microenvironment are current goals of cancer therapy. However, components of canonical autophagy play roles in other biological processes, adding ...complexity to this goal. One such alternative function of autophagy proteins is LC3-associated phagocytosis (LAP), which functions in phagosome maturation and subsequent signaling events. Here, we show that impairment of LAP in the myeloid compartment, rather than canonical autophagy, induces control of tumor growth by tumor-associated macrophages (TAM) upon phagocytosis of dying tumor cells. Single-cell RNA sequencing (RNA-seq) analysis revealed that defects in LAP induce pro-inflammatory gene expression and trigger STING-mediated type I interferon responses in TAM. We found that the anti-tumor effects of LAP impairment require tumor-infiltrating T cells, dependent upon STING and the type I interferon response. Therefore, autophagy proteins in the myeloid cells of the tumor microenvironment contribute to immune suppression of T lymphocytes by effecting LAP.
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•LAP occurs as dead cells are engulfed in the tumor microenvironment•TAM lacking LAP display M1 characteristics and compromise tumors•TAM lacking LAP engage STING-dependent type I IFN production•TAM lacking LAP promote anti-tumor T cell responses
Impairment of LC3-associated phagocytosis in myeloid cells of the tumor microenvironment has anti-tumor effects.
Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. ...The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (Tregs) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in Treg responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in "sensing" protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.
Parkinson’s disease is a degenerative, chronic and progressive disease, characterized by motor dysfunctions. Patients also exhibit non-motor symptoms, such as affective and sleep disorders. Sleep ...disorders can potentiate clinical and neuropathological features and lead to worse prognosis. The goal of this study was to evaluate the effects of sleep deprivation (SD) in mice submitted to a progressive pharmacological model of Parkinsonism (chronic administration with a low dose of reserpine). Male Swiss mice received 20 injections of reserpine (0.1 mg/kg) or vehicle, on alternate days. SD was applied before or during reserpine treatment and was performed by gentle handling for 6 h per day for 10 consecutive days. Animals were submitted to motor and non-motor behavioral assessments and neurochemical evaluations. Locomotion was increased by SD and decreased by reserpine treatment. SD during treatment delayed the onset of catalepsy, but SD prior to treatment potentiated reserpine-induced catalepsy. Thus, although SD induced an apparent beneficial effect on motor parameters, a delayed deleterious effect on alterations induced by reserpine was found. In the object recognition test, both SD and reserpine treatment produced cognitive deficits. In addition, the association between SD and reserpine induced anhedonic-like behavior. Finally, an increase in oxidative stress was found in hippocampus of mice subjected to SD, and tyrosine hydroxylase immunoreactivity was reduced in substantia nigra of reserpine-treated animals. Results point to a possible late effect of SD, aggravating the deficits in mice submitted to the reserpine progressive model of PD.
Abstract
Spatial arrangement of distinct Amazonian environments through time and its effect on specialized biota remain poorly known, fueling long-lasting debates about drivers of biotic ...diversification. We address the late Quaternary sediment deposition that assembled the world's largest seasonally flooded ecosystems. Genome sequencing was used to reconstruct the demographic history of bird species specialized in either early successional vegetation or mature floodplain forests. Sediment deposition that built seasonally flooded habitats accelerated throughout the Holocene (last 11,700 years) under sea level highstand and intensification of the South American Monsoon, at the same time as global increases in atmospheric methane concentration. Bird populations adapted to seasonally flooded habitats expanded due to enlargement of Amazonian river floodplains and archipelagos. Our findings suggest that the diversification of the biota specialized in seasonally flooded habitats is coupled to sedimentary budget changes of large rivers, which rely on combined effects of sea level and rainfall variations.
Legionella pneumophila is a Gram-negative, flagellated bacterium that survives in phagocytes and causes Legionnaires' disease. Upon infection of mammalian macrophages, cytosolic flagellin triggers ...the activation of Naip/NLRC4 inflammasome, which culminates in pyroptosis and restriction of bacterial replication. Although NLRC4 and caspase-1 participate in the same inflammasome, Nlrc4-/- mice and their macrophages are more permissive to L. pneumophila replication compared with Casp1/11-/-. This feature supports the existence of a pathway that is NLRC4-dependent and caspase-1/11-independent. Here, we demonstrate that caspase-8 is recruited to the Naip5/NLRC4/ASC inflammasome in response to flagellin-positive bacteria. Accordingly, caspase-8 is activated in Casp1/11-/- macrophages in a process dependent on flagellin, Naip5, NLRC4 and ASC. Silencing caspase-8 in Casp1/11-/- cells culminated in macrophages that were as susceptible as Nlrc4-/- for the restriction of L. pneumophila replication. Accordingly, macrophages and mice deficient in Asc/Casp1/11-/- were more susceptible than Casp1/11-/- and as susceptible as Nlrc4-/- for the restriction of infection. Mechanistically, we found that caspase-8 activation triggers gasdermin-D-independent pore formation and cell death. Interestingly, caspase-8 is recruited to the Naip5/NLRC4/ASC inflammasome in wild-type macrophages, but it is only activated when caspase-1 or gasdermin-D is inhibited. Our data suggest that caspase-8 activation in the Naip5/NLRC4/ASC inflammasome enable induction of cell death when caspase-1 or gasdermin-D is suppressed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Expansins refer to a family of closely related non-enzymatic proteins found in the plant cell wall that are involved in the cell wall loosening. In addition, expansins appear to be involved in ...different physiological and environmental responses in plants such as leaf and stem initiation and growth, stomata opening and closing, reproduction, ripening and stress tolerance. Sugarcane (Saccharum spp.) is one of the main crops grown worldwide. Lignocellulosic biomass from sugarcane is one of the most promising raw materials for the ethanol industry. However, the efficient use of lignocellulosic biomass requires the optimization of several steps, including the access of some enzymes to the hemicellulosic matrix. The addition of expansins in an enzymatic cocktail or their genetic manipulation could drastically improve the saccharification process of feedstock biomass by weakening the hydrogen bonds between polysaccharides present in plant cell walls. In this study, the expansin gene family in sugarcane was identified and characterized by in silico analysis. Ninety two putative expansins in sugarcane (SacEXPs) were categorized in three subfamilies after phylogenetic analysis. The expression profile of some expansin genes in leaves of sugarcane in different developmental stages was also investigated. This study intended to provide suitable expansin targets for genetic manipulation of sugarcane aiming at biomass and yield improvement.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Key points
Fish oil (FO), rich in omega‐3 polyunsaturated fatty acids, has beneficial effects on changes induced by obesity and partially prevents associated comorbidities.
The effects of FO on ...adipocytes from different adipose tissue depots in high‐fat (HF) diet induced obese mice have not been uninvestigated.
This is the first study to examine the effects of FO on changes in metabolism and adipokine production in adipocytes from s.c. (inguinal; ING) or visceral (retroperitoneal; RP) white adipose depots in a HF diet‐induced obese mice.
Unlike most studies performed previously, FO supplementation was initiated 4 weeks before the induction of obesity.
HF diet caused marked changes in ING (glucose uptake and secretion of adiponectin, tumour necrosis factor‐α and interleukin‐6 in ING) and RP (lipolysis, de novo lipogenesis and secretion of pro‐inflammatory cytokines) adipose depots.
Previous and concomitant FO administration prevented the changes in ING and RP adipocytes induced by the HF diet.
In the present study, we investigated the effect of fish oil (FO) on metabolism and adipokine production by adipocytes from s.c. (inguinal; ING) and visceral (retroperitoneal; RP) white adipose depots in high‐fat (HF) diet‐induced obese mice. Mice were divided into CO (control diet), CO+FO, HF and HF+FO groups. The HF group presented higher body weight, glucose intolerance, insulin resistance, higher plasma total and low‐density lipoprotein cholesterol levels, and greater weights of ING and RP adipose depots accompanied by hypertrophy of the adipocytes. FO exerted anti‐obesogenic effects associated with beneficial effects on dyslipidaemia and insulin resistance in mice fed a HF diet (HF+FO group). HF raised RP adipocyte lipolysis and the production of pro‐inflammatory cytokines and reduced de novo synthesis of fatty acids, whereas, in ING adipocytes, it decreased glucose uptake and adiponectin secretion but did not change lipolysis. Therefore, the adipose depots play different roles in HF diet‐induced insulin resistance according to their location in the body. Concerning cytokine secretion, adipocytes per se in addition to white adopise tissue infiltrated leukocytes have to be considered in the aetiology of the comorbidities associated with obesity. Evidence is presented showing that previous and concomitant administration of FO can prevent changes in metabolism and the secretion of hormones and cytokines in ING and RP adipocytes induced by HF.
Key points
Fish oil (FO), rich in omega‐3 polyunsaturated fatty acids, has beneficial effects on changes induced by obesity and partially prevents associated comorbidities.
The effects of FO on adipocytes from different adipose tissue depots in high‐fat (HF) diet induced obese mice have not been uninvestigated.
This is the first study to examine the effects of FO on changes in metabolism and adipokine production in adipocytes from s.c. (inguinal; ING) or visceral (retroperitoneal; RP) white adipose depots in a HF diet‐induced obese mice.
Unlike most studies performed previously, FO supplementation was initiated 4 weeks before the induction of obesity.
HF diet caused marked changes in ING (glucose uptake and secretion of adiponectin, tumour necrosis factor‐α and interleukin‐6 in ING) and RP (lipolysis, de novo lipogenesis and secretion of pro‐inflammatory cytokines) adipose depots.
Previous and concomitant FO administration prevented the changes in ING and RP adipocytes induced by the HF diet.
The valuation of ecosystem services of pollution regulation in basins with partial monitoring does not have only one consolidated methodology which can be applied in all countries, biomes and across ...spatio-temporal scales. While different metrics can incorporate elements of uncertainty for decision makers, changes in land use, climate and sectoral demands in basins increase the need for the efficiency and complexity of valuation methods. Here, based on adapting a pre-existing method, we present a new ecosystem service valuation applied to river basins under different characteristics in the biomes of the Atlantic Forest and Brazilian savannah. Our assumptions of ecosystem service valuation concern an analogy based on willingness-to-pay for not marketable services, but adapted by data from the river basins' ecohydrological monitoring. First, the method depicts river ecosystem valuation with probabilistic criteria of both the water yield, as supply, and the grey Water Footprint (greyWF), as demand. Second, we introduced the comparison between water supply and demand carried out on the continuous flow regime and monitored loads in rivers with different land uses, sizes and biomes. Third, this new ecosystem service valuation method enabled us to quickly visualize the possible stages of sustainability concerning the Brazilian legal framework among different basins. The methodology was applied in 12 Brazilian river basins, with drainage areas between 17 and 26,500 km2, and changes in land use with variable percentages of urban (62–92%), forest (51–84%) and agriculture (51–89%) areas. The most polluted basins, with greyWF values far above those allowed, have the most significant, almost asymptotic valuation curves. Results range from a minimum reference value of 61 US$/ha/year for conservation, adapted from the Brazilian Water Producer, to US$ 330 for restoring high polluted basins. The results show the viability of this method and discuss further opportunities for water security, especially for climate change and non-stationary sectorial demands.
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•A new valuation of regulating ecosystem services for river regimes is presented.•Regulating services are viewed from probabilistic analogy of economic supply & demand, as watershed degradation through greyWF.•The method is applied in 12 Brazilian watersheds with drainage areas ranging from 17 to 26,500 km2.•According to greyWF, greyWFref and Qlp, valuations were grouped in 3 categories regarded to river regime and water pollution.•This method can be adapted for climate change and non-stationary water demands.
•Discrete version of the Hutchinson-Barnsley theory providing algorithms to approximate the Hutchinson measure for generalized and classical iterated function systems.•Discrete version of the ...deterministic algorithm for fractal drawing.•Discrete Markov operators.•Invariant measures, Hutchinson measures, fractal attractors.•Discrete deterministic algorithms.
We introduce a discrete version of the Hutchinson–Barnsley theory providing algorithms to approximate the Hutchinson measure for iterated function systems (IFS) and generalized iterated function systems (GIFS), complementing the discrete version of the deterministic algorithm considered in our previous work.
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