The role of mitochondria in NLRP3 inflammasome activation.

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)

The receptors of the innate immune system detect specific microbial ligands to promote effective inflammatory and adaptive immune responses. Although this idea is well appreciated, studies in recent years have highlighted the complexity of innate immune detection, with multiple host receptors recognizing the same microbial ligand. Understanding the collective actions of diverse receptors that recognize common microbial signatures represents a new frontier in the study of innate immunity, and is the focus of this Review. Here, we discuss examples of individual bacterial cell wall components that are recognized by at least two and as many as four different receptors of the innate immune system. These receptors survey the extracellular or cytosolic spaces for their cognate ligands and operate in a complementary manner to induce distinct cellular responses. We further highlight that, despite this genetic diversity in receptors and pathways, common features exist to explain the operation of these receptors. These common features may help to provide unifying organizing principles associated with host defence.

Multi-receptor detection of individual bacterial products by the innate immune system

The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure. Ultimately, studies continue to reveal how the ATP-binding and hydrolysis properties of NACHT domains in different NLRs integrate with signaling modules and binding partners to control innate immune responses at the molecular level.

ATP-Binding and Hydrolysis in Inflammasome Activation.

Nucleotide-binding oligomerization domain (NOD) and leucine-rich repeat (LRR)-containing receptors or NOD-like receptors (NLRs) are cytosolic pattern recognition receptors which sense conserved microbial patterns and host-derived danger signals to elicit innate immune responses. The activation of several prototypic NLRs, including NLR and pyrin domain (PYD) containing (NLRP) 1, NLRP3 and NLR and caspase recruitment domain (CARD) containing (NLRC) 4, results in the assembly of inflammasomes which are large, cytoplasmic multi-protein signaling platforms responsible for the maturation and release of the pro-inflammatory cytokines IL-1β and IL-18, and for the induction of a specialized form of inflammatory cell death called pyroptosis. However, the function of other members of the NLR family, including NLRP7, are less well understood. NLRP7 has been linked to innate immune signaling, but its precise role is still controversial as it has been shown to positively and negatively affect inflammasome responses. Inflammasomes are essential for homeostasis and host defense, but inappropriate inflammasome responses due to hereditary mutations and somatic mosaicism in inflammasome components and defective regulation has been linked to a broad spectrum of human diseases. A compelling connection between NLRP7 mutations and reproductive diseases, and in particular molar pregnancy, has been established. Though, the molecular mechanisms by which NLRP7 mutations contribute to reproductive diseases are largely unknown. In this review, we focus on NLRP7 and discuss the current evidence of its role in inflammasome regulation as well as its implication in human reproductive diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/imm.13372

NLRP7: From inflammasome regulation to human disease

Mycobacterium bovis is the causative agent of tuberculosis in cattle. Infection of macrophages with M. bovis leads to the activation of the “nucleotide binding and oligomerization, leucine-rich repeat and pyrin domains-containing protein 3” (NLRP3) and “absent in melanoma 2” (AIM2) inflammasomes, which in turn triggers release of the proinflammatory cytokine interleukin-1β (IL-1β) that contributes to bacterial clearance and plays a crucial role in the host defense. However, NLRP3 and AIM2 inflammasome activation is influenced by several factors and how IL-1β secretion by M. bovis-infected macrophages is regulated via the inflammasome pathway remains unclear. Here we found that IL-1β secretion and pro-IL-1β protein accumulation were inhibited in THP-1 macrophages upon exposure to the virulent M. bovis Beijing strain in the presence of high K+ concentrations, cycloheximide (a protein synthesis inhibitor) and PR-619 (a deubiquitinating enzyme inhibitor). Scavenging reactive oxygen species (ROS) induced by N-acetylcysteine reduced IL-1β release independent of the mitochondrial permeability transition. Collectively, our results suggest that IL-1β secretion by M. bovis-infected THP-1 macrophages is reduced by high extracellular K+ concentration, inhibition of new protein synthesis, deubiquitination, and ROS generation.

Inflammasomes-dependent regulation of IL-1β secretion induced by the virulent Mycobacterium bovis Beijing strain in THP-1 macrophages.

The ability of mycobacteria to grow and invade target tissues is the key component in the process of Mycobacterium bovis infection. Therefore, analysis of the proteins responsible for cell invasion will assist clinicians in combating bovine tuberculosis. The Mb1514 gene of M. bovis encodes a hypothetical invasion protein (designated here as MbINV protein), whose function has not yet been directly identified. In this study, the Mb1514 gene from M. bovis was cloned, and expressed in E. coli. The recombinant MbINV protein (a single band of approximately 28 kDa) was purified for biological analysis. Our data demonstrated that recombinant MbINV protein significantly inhibited the viability of RAW264.7 macrophages in a dose-dependent manner (P < 0.05), and induced cell necrosis, indicating that the protein is toxic. MbINV protein infection significantly enhanced the mRNA expression levels of TNF-α, IL-1β, and NOS2 (P < 0.01), suggesting that MbINV protein may be one of the virulence factors which directly interact with macrophages and modulate the host immune response to M. bovis. An invasion inhibition assay showed that MbINV-inhibited M. bovis invasion of RAW264.7 cells in a concentration-dependant manner, demonstrating it is an invasion protein.

https://link.springer.com/content/pdf/10.1007%2Fs11010-013-1813-5.pdf

Prokaryotic expression and functional analysis of the Mb1514 gene in Mycobacterium bovis

Mycobacterium bovis is the causative agent of tuberculosis in a wide range of mammals, including humans. Macrophages are the first line of host defense. They secrete proinflammatory cytokines, such as interleukin-1 beta (IL-1β), in response to mycobacterial infection, but the underlying mechanisms by which human macrophages are activated and release IL-1β following M. bovis infection are poorly understood. Here we show that the 'nucleotide binding and oligomerization of domain-like receptor (NLR) family pyrin domain containing 7 protein' (NLRP7) inflammasome is involved in IL-1β secretion and caspase-1 activation induced by M. bovis infection in THP-1 macrophages. NLRP7 inflammasome activation promotes the induction of pyroptosis as well as the expression of tumor necrosis factor alpha (TNF-α), Chemokine (C-C motif) ligand 3 (CCL3) and IL-1β mRNAs. Thus, the NLRP7 inflammasome contributes to IL-1β secretion and induction of pyroptosis in response to M. bovis infection in THP-1 macrophages.

/pdf/virulent-mycobacterium-bovis-beijing-strain-activates-the-1kcgdp3ox1.pdf

Virulent Mycobacterium bovis Beijing Strain Activates the NLRP7 Inflammasome in THP-1 Macrophages

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Inflammasomes-dependent regulation of IL-1β secretion induced by the virulent Mycobacterium bovis Beijing strain in THP-1 macrophages.

Prokaryotic expression and functional analysis of the Mb1514 gene in Mycobacterium bovis

Virulent Mycobacterium bovis Beijing Strain Activates the NLRP7 Inflammasome in THP-1 Macrophages