Cell death is a fundamental biological phenomenon that is essential for the survival and development of an organism. Emerging evidence also indicates that cell death contributes to immune defense against infectious diseases. Pyroptosis is a form of inflammatory programmed cell death pathway activated by human and mouse caspase-1, human caspase-4 and caspase-5, or mouse caspase-11. These inflammatory caspases are used by the host to control bacterial, viral, fungal, or protozoan pathogens. Pyroptosis requires cleavage and activation of the pore-forming effector protein gasdermin D by inflammatory caspases. Physical rupture of the cell causes release of the pro-inflammatory cytokines IL-1β and IL-18, alarmins and endogenous danger-associated molecular patterns, signifying the inflammatory potential of pyroptosis. Here, we describe the central role of inflammatory caspases and pyroptosis in mediating immunity to infection and clearance of pathogens.

Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases.

Macrophages mediate crucial innate immune responses via caspase-1-dependent processing and secretion of IL-1β and IL-18. While wild type Salmonella typhimurium infection is lethal to mice, a strain that persistently expresses flagellin was cleared by the cytosolic flagellin detection pathway via NLRC4 activation of caspase-1; however, this clearance was independent of IL-1β and IL-18. Instead, caspase-1 induced pyroptotic cell death released bacteria from macrophages, exposing them to uptake and killing by reactive oxygen species in neutrophils. Similarly, caspase-1 cleared Legionella and Burkholderia by cytokine independent mechanisms. Our results show, for the first time, that caspase-1 can clear intracellular bacteria in vivo independent of IL-1β and IL-18, and establish pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system.

Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria (111.33)

Inflammatory caspases play a central role in innate immunity by responding to cytosolic signals and initiating a twofold response. First, caspase-1 induces the activation and secretion of the two prominent pro-inflammatory cytokines, interleukin-1β (IL-1β) and IL-18. Second, either caspase-1 or caspase-11 can trigger a form of lytic, programmed cell death called pyroptosis. Pyroptosis operates to remove the replication niche of intracellular pathogens, making them susceptible to phagocytosis and killing by a secondary phagocyte. However, aberrant, systemic activation of pyroptosis in vivo may contribute to sepsis. Emphasizing the efficiency of inflammasome detection of microbial infections, many pathogens have evolved to avoid or subvert pyroptosis. This review focuses on molecular and morphological characteristics of pyroptosis and the individual inflammasomes and their contribution to defense against infection in mice and humans.

Pyroptotic cell death defends against intracellular pathogens

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.26592

NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice.

Eukaryotic cells can die from physical trauma, which results in necrosis. Alternatively, they can die through programmed cell death upon the stimulation of specific signalling pathways. In this Review, we discuss the role of different cell death pathways in innate immune defence against bacterial and viral infection: apoptosis, necroptosis, pyroptosis and NETosis. We describe the interactions that interweave different programmed cell death pathways, which create complex signalling networks that cross-guard each other in the evolutionary 'arms race' with pathogens. Finally, we describe how the resulting cell corpses - apoptotic bodies, pore-induced intracellular traps (PITs) and neutrophil extracellular traps (NETs) - promote the clearance of infection.

/pdf/programmed-cell-death-as-a-defence-against-infection-3xmfkor9mf.pdf

Programmed cell death as a defence against infection.

The inflammasome is an important innate immune pathway that regulates at least two host responses protective against infections: (1) secretion of the proinflammatory cytokines IL-1β and IL-18 and (2) induction of pyroptosis, a form of cell death. Inflammasomes, of which different types have been identified, are multiprotein complexes containing pattern recognition receptors belonging to the Nod-like receptor family or the PYHIN family and the protease caspase-1. The molecular aspects involved in the activation of different inflammasomes by various pathogens are being rapidly elucidated, and their role during infections is being characterized. Production of IL-1β and IL-18 and induction of pyroptosis of the infected cell have been shown to be protective against many infectious agents. Here, we review the recent literature concerning inflammasome activation in the context of bacterial infections and identify important questions to be answered in the future.

/pdf/role-of-the-inflammasome-il-1b-and-il-18-in-bacterial-1r9dtvsv9c.pdf

Role of the Inflammasome, IL-1β, and IL-18 in Bacterial Infections

Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and other cell types and causes melioidosis. The interaction of B. pseudomallei with the inflammasome and the role of pyroptosis, IL-1β, and IL-18 during melioidosis have not been investigated in detail. Here we show that the Nod-like receptors (NLR) NLRP3 and NLRC4 differentially regulate pyroptosis and production of IL-1β and IL-18 and are critical for inflammasome-mediated resistance to melioidosis. In vitro production of IL-1β by macrophages or dendritic cells infected with B. pseudomallei was dependent on NLRC4 and NLRP3 while pyroptosis required only NLRC4. Mice deficient in the inflammasome components ASC, caspase-1, NLRC4, and NLRP3, were dramatically more susceptible to lung infection with B. pseudomallei than WT mice. The heightened susceptibility of Nlrp3-/- mice was due to decreased production of IL-18 and IL-1β. In contrast, Nlrc4-/- mice produced IL-1β and IL-18 in higher amount than WT mice and their high susceptibility was due to decreased pyroptosis and consequently higher bacterial burdens. Analyses of IL-18-deficient mice revealed that IL-18 is essential for survival primarily because of its ability to induce IFNγ production. In contrast, studies using IL-1RI-deficient mice or WT mice treated with either IL-1β or IL-1 receptor agonist revealed that IL-1β has deleterious effects during melioidosis. The detrimental role of IL-1β appeared to be due, in part, to excessive recruitment of neutrophils to the lung. Because neutrophils do not express NLRC4 and therefore fail to undergo pyroptosis, they may be permissive to B. pseudomallei intracellular growth. Administration of neutrophil-recruitment inhibitors IL-1ra or the CXCR2 neutrophil chemokine receptor antagonist antileukinate protected Nlrc4-/- mice from lethal doses of B. pseudomallei and decreased systemic dissemination of bacteria. Thus, the NLRP3 and NLRC4 inflammasomes have non-redundant protective roles in melioidosis: NLRC4 regulates pyroptosis while NLRP3 regulates production of protective IL-18 and deleterious IL-1β.

/pdf/inflammasome-dependent-pyroptosis-and-il-18-protect-against-4a8n840uko.pdf

Inflammasome-dependent Pyroptosis and IL-18 Protect against Burkholderia pseudomallei Lung Infection while IL-1β Is Deleterious

Simple Summary Creole goat milk is a valuable product for human consumption. Its physicochemical characteristics could be influenced by altitude and lactation stage. In this work, we evaluated several chemical and physical conditions of Creole goat milk in semiarid rangeland. The main results indicated that protein and density are influenced by altitude, while fat, freezing point, and pH are influenced by the lactation stage. One of the most nutritional values of goat milk is the type and concentration of fatty acids. In this work, we found that the effect of the agroecological region was minimal on their concentration. The lactation stage affected the composition of medium-chain fatty acids and linoelaidic acid. We concluded that nutrition by altitude and goat genetic background could contribute to milk composition. Abstract Goat milk composition is affected by feeding, and in semiarid rangeland, information on Creole goat milk physicochemical composition is lacking. For the fulfillment of this objective, three agroecological regions (AR) considering altitude (lowland 87, highland 779, and mountain 1309 m above sea level) with different botanical compositions were chosen. Every AR analyzed accounted for 30 goat herds, with a total of 90 herds. The results demonstrated that altitude had an influence mainly on density and protein. Milk density increases as altitude increases; conversely, milk protein increases as altitude decreases. On the other hand, in the mountain and lowland ARs, the salts and solids not fat (SNF) percentages were higher compared to that of the highland AR (p < 0.05). The freezing point (FP) was higher at highland altitudes compared to that of mountain and lowland ARs (p < 0.01). In the milk fatty acids (FA) profile, only the C14:1 value was affected by altitude, whereas goat milk at lowland and mountain altitudes had higher values compared to that at highland altitudes (p < 0.05). Additionally, late lactation stage fat, FP, and pH values were higher compared to early lactation values. The opposite effect was observed for salts and SNF. In the FA profile, late lactation values were higher for C10:0 and C8:0 compared to early lactation values. The opposite trend was observed for C18:2n6t. The thrombogenic index was significantly higher at lowland altitudes compared to highland altitudes, and similar to the mountain AR. These goat milk characteristics could be explained as a consequence of animal nutrition, as well as the goat’s meat-type phenotype.

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Ivonne Ceballos-Olvera

Papers

Role of the Inflammasome, IL-1β, and IL-18 in Bacterial Infections

Inflammasome-dependent Pyroptosis and IL-18 Protect against Burkholderia pseudomallei Lung Infection while IL-1β Is Deleterious

Milk Composition of Creole Goats Raised at Different Altitudes in an Extensive Production System in Northeast Mexico