Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1 secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1 in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1 was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1 and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1 by antigen-presenting cells in an NLRP3-and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1 in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1 through at least two separate mechanisms: by targeting pro-IL-1 for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.IL-1 is an important proinflammatory cytokine, released at sites of infection or injury, that regulates diverse physiological responses, including cellular recruitment, appetite, sleep, and body temperature (1). IL-1 is first produced as a proform in response to inflammatory stimuli, such as TLR ligands. This inactive precursor is cleaved into the bioactive (p17) molecule by caspase 1, following the activation of an inflammasome (2).Inflammasomes are molecular scaffolds that trigger the activation of caspase 1 and subsequent maturation of IL-1 and IL-18. Typically, inflammasomes are formed from at least one member of the cytosolic innate immune sensor family, the NOD-like receptors (NLRs), including NLRP1, NLRP3, and NLRC4, coupled with the adaptor apoptosis-associated specklike protein containing a caspase recruitment domain (ASC or PYCARD) and caspase 1 (2). The NLRP3 inflammasome is the best characterized to date and is activated by a number of endogenous and exogenous signals.Most studies in vitro employ TLR ligands, particularly LPS, to induce pro-IL-1 formation, but in many cases, this is not enough to stimulate inflammasome activation and secretion of the mature cytokine. Instead, a second signal is commonly required, and this can come from a number of endogenous and exogenous sources, including ATP and particulates, including uric acid crystals, amyloid-, silica, asbestos, synthetic microparticles, and alum (3-8). Extracellular ATP triggers the P2X7 ATP-gated ion channel, leading to K ϩ efflux and induces recruitment of the pannexin-1 membrane pore (9). This may then allow extracellular NLRP3 agonists to enter the cell and activate inflammasome assembly (9). Particulates have been proposed to act through one of two mechanisms. Uptake of particulates by phagocytes may lead to lysosomal damage and release of lysosomal products into the cytosol, which a...
Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects alveolar macrophages following aerosol transmission. Lung macrophages provide a critical intracellular niche that is required for Mtb to establish infection in the human host. This parasitic relationship is made possible by the capacity of Mtb to block phagosome maturation following entry into the host macrophage, creating an environment that supports bacillary replication. Apoptosis is increasingly understood to play a role in host defense against intracellular pathogens including viruses, fungi, protozoa and bacteria. In the last 15 years an understanding of the role that macrophage apoptosis plays in TB has begun to emerge. Here we review the history and current state of the art of this topic and we offer a model of the macrophage-pathogen interaction that takes into the account the complexities of programmed cell death and the relationship between various death signaling pathways and host defense in TB.
Sayitoglu et al. Boosting NK Cell-Mediated Sarcoma Targeting cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1 + or NKG2D + GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies.
To characterize the metabolic role of peroxisomes in yeast cells under physiological conditions, we performed a comprehensive meta-analysis of published microarray data. Previous studies of yeast peroxisomes have mainly been focused on the function of peroxisomes under extreme conditions, such as growth on oleate or methanol as the sole carbon source, and may therefore not be representative of the normal physiological role of yeast peroxisomes. Surprisingly, our analysis of the microarray data reveals that the only pathway responding to peroxisome deficiency in mid-log phase is lysine biosynthesis, whereas classical peroxisomal pathways such as beta-oxidation are unaffected. We show that the upregulation of lysine biosynthesis genes in peroxisome-deficient yeasts shares many characteristics with the physiological response to lysine starvation. We provide data that suggest that this is the result of a "pathological" stimulation of the Lys14p transcriptional activator by the pathway intermediate aminoadipate semialdehyde. Mistargeting of the peroxisomal lysine pathway to the cytosol increases the active concentration of aminoadipate semialdehyde, which is no longer contained in the peroxisome and can now activate Lys14p at much lower levels than in wild-type yeasts. This is the first well-documented example of pathway misregulation in response to peroxisome deficiency and will be useful in understanding the phenotypic details of human peroxisome-deficient patients (Zellweger syndrome).Peroxisomes are single-membrane-bounded organelles present in most eukaryotic cells, with the exception of Plasmodium, Giardia, Trichomonas, Entamoeba, and related species. Peroxisomes typically contain the enzymes of fatty acid betaoxidation and catalase, which converts the hydrogen peroxide formed by fatty acyl-coenzyme A (CoA) oxidase to water and oxygen. Several other oxidases, e.g., monoamine oxidase, urate oxidase, hydroxyacid oxidase, methanol oxidase, and acetylspermidine oxidase, are also present in peroxisomes of some species and benefit from the same detoxification mechanism. In addition to these oxidative reactions, peroxisomes may contain many other biosynthetic pathways. Enzymes of these supplemental pathways are usually absent or localized in nonperoxisomal compartments in most eukaryotes, and their peroxisomal localization is a specialization of relatively few species. Examples of facultative peroxisomal pathways are glycolysis and purine salvage (in the peroxisomes of kinetoplastids, such as Trypanosoma and Leishmania [23]), isoprenoid biosynthesis (in vertebrates [1]), ether phospholipid biosynthesis (in kinetoplastids and animals [15,33]), and the glyoxylate cycle, which channels the products of beta-oxidation into gluconeogenesis in plants, yeasts, and Caenorhabditis elegans (7).Peroxisome-deficient mutants of most organisms are viable (with the possible exception of kinetoplastids), but a lack of functional peroxisomes can lead to severe pathologies in multicellular organisms (3,5,8,16,20,24). In all organisms ex...
A high intracellular bacillary load of Mycobacterium tuberculosis in macrophages induces an atypical lysosomal cell death with early features of apoptosis that progress to necrosis within hours. Unlike classical apoptosis, this cell death mode does not appear to diminish M. tuberculosis viability. We previously reported that culturing heavily infected macrophages with naïve macrophages produced an antimicrobial effect, but only if naïve macrophages were added during the pre-necrotic phase of M. tuberculosis-induced cell death. In the present study we investigated the mechanism of antimicrobial activity in co-cultures, anticipating that efferocytosis of bacilli in apoptotic bodies would be required. Confocal microscopy revealed frustrated phagocytosis of M. tuberculosis-infected macrophages with no evidence that significant numbers of bacilli were transferred to the naïve macrophages. The antimicrobial effect of naïve macrophages was retained when they were separated from infected macrophages in transwells, and conditioned co-culture supernatants transferred antimicrobial activity to cultures of infected macrophages alone. Antimicrobial activity in macrophage co-cultures was abrogated when the naïve population was deficient in IL-1 receptor or when the infected population was deficient in inducible nitric oxide synthase. The participation of nitric oxide suggested a conventional antimicrobial mechanism requiring delivery of bacilli to a late endosomal compartment. Using macrophages expressing GFP-LC3 we observed the induction of autophagy specifically by a high intracellular load of M. tuberculosis. Bacilli were identified in LC3-positive compartments and LC3-positive compartments were confirmed to be acidified and LAMP1 positive. Thus, the antimicrobial effect of naïve macrophages acting on M. tuberculosis in heavily-infected macrophages is contact-independent. Interleukin-1 provides an afferent signal that induces an as yet unidentified small molecule which promotes nitric oxide-dependent antimicrobial activity against bacilli in autolysosomes of heavily infected macrophages. This cooperative, innate antimicrobial interaction may limit the maximal growth rate of M. tuberculosis prior to the expression of adaptive immunity in pulmonary tuberculosis.
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