Guanylate-binding proteins: mechanisms of pattern recognition and antimicrobial functions.

Guanylate-binding proteins (GBPs) are a family of intracellular proteins which have diverse biological functions, including pathogen sensing and host defense against infectious disease. These proteins are expressed in response to interferon (IFN) stimulation and can localize and target intracellular microbes (e.g., bacteria and viruses) by protein trafficking and membrane binding. These properties contribute to the ability of GBPs to induce inflammasome activation, inflammation, and cell death, and to directly disrupt pathogen membranes. Recent biochemical studies have revealed that human GBP1, GBP2, and GBP3 can directly bind to the lipopolysaccharide (LPS) of Gram-negative bacteria. In this review we discuss emerging data highlighting the functional versatility of GBPs, with a focus on their molecular mechanisms of pattern recognition and antimicrobial activity.

Immunity against Moraxella catarrhalis requires guanylate-binding proteins and caspase-11-NLRP3 inflammasomes.

Moraxella catarrhalis is an important human respiratory pathogen and a major causative agent of otitis media and chronic obstructive pulmonary disease. Toll-like receptors contribute to, but cannot fully account for, the complexity of the immune response seen in M. catarrhalis infection. Using primary mouse bone marrow-derived macrophages to examine the host response to M. catarrhalis infection, our global transcriptomic and targeted cytokine analyses revealed activation of immune signalling pathways by both membrane-bound and cytosolic pattern-recognition receptors. We show that M. catarrhalis and its outer membrane vesicles or lipooligosaccharide (LOS) can activate the cytosolic innate immune sensor caspase-4/11, gasdermin-D-dependent pyroptosis, and the NLRP3 inflammasome in human and mouse macrophages. This pathway is initiated by type I interferon signalling and guanylate-binding proteins (GBPs). We also show that inflammasomes and GBPs, particularly GBP2, are required for the host defence against M. catarrhalis in mice. Overall, our results reveal an essential role for the interferon-inflammasome axis in cytosolic recognition and immunity against M. catarrhalis, providing new molecular targets that may be used to mitigate pathological inflammation triggered by this pathogen.

Molecular mechanisms activating the NAIP-NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer.

Cytosolic innate immune sensing is a cornerstone of innate immunity in mammalian cells and provides a surveillance system for invading pathogens and endogenous danger signals. The NAIP-NLRC4 inflammasome responds to cytosolic flagellin, and the inner rod and needle proteins of the type 3 secretion system of bacteria. This complex induces caspase-1-dependent proteolytic cleavage of the proinflammatory cytokines IL-1ß and IL-18, and the pore-forming protein gasdermin D, leading to inflammation and pyroptosis, respectively. Localized responses triggered by the NAIP-NLRC4 inflammasome are largely protective against bacterial pathogens, owing to several mechanisms, including the release of inflammatory mediators, liberation of concealed intracellular pathogens for killing by other immune mechanisms, activation of apoptotic caspases, caspase-7, and caspase-8, and expulsion of an entire infected cell from the mammalian host. In contrast, aberrant activation of the NAIP-NLRC4 inflammasome caused by de novo gain-of-function mutations in the gene encoding NLRC4 can lead to macrophage activation syndrome, neonatal enterocolitis, fetal thrombotic vasculopathy, familial cold autoinflammatory syndrome, and even death. Some of these clinical manifestations could be treated by therapeutics targeting inflammasome-associated cytokines. In addition, the NAIP-NLRC4 inflammasome has been implicated in the pathogenesis of colorectal cancer, melanoma, glioma, and breast cancer. However, no consensus has been reached on its function in the development of any cancer types. In this review, we highlight the latest advances in the activation mechanisms and structural assembly of the NAIP-NLRC4 inflammasome, and the functions of this inflammasome in different cell types. We also describe progress toward understanding the role of the NAIP-NLRC4 inflammasome in infectious diseases, autoinflammatory diseases, and cancer.

Running to save sight: The effects of exercise on retinal health and function.

The benefits of exercise to human health have long been recognised. However, only in the past decade have researchers started to discover the molecular benefits that exercise confers, especially to the central nervous system (CNS). These discoveries include the magnitude of molecular messages that are communicated from skeletal muscle to the CNS. Despite these advances in understanding, very limited studies have been conducted to decipher the molecular benefits of exercise in retinal health and disease. Here, we review the latest work on the effects of exercise on the retina and discuss its effects on the wider CNS, with a focus on demonstrating the potential applicability and comparative molecular mechanisms that may be occurring in the retina. This review covers the key molecular pathways where exercise exerts its effects: oxidative stress and mitochondrial health; inflammation; protein aggregation; neuronal health; and tissue crosstalk via extracellular vesicles. Further research on the benefits of exercise to the retina and its molecular messages within extracellular vesicles is highly topical in this field.

Voluntary exercise modulates pathways associated with amelioration of retinal degenerative diseases.

Background: Exercise has been shown to promote a healthier and longer life and linked to a reduced risk of developing neurodegenerative diseases including retinal degenerations. However, the molecular pathways underpinning exercise-induced cellular protection are not well understood. In this work we aim to profile the molecular changes underlying exercise-induced retinal protection and investigate how exercise-induced inflammatory pathway modulation may slow the progression of retinal degenerations. Methods: Female C57Bl/6J mice at 6 weeks old were given free access to open voluntary running wheels for a period of 28 days and then subjected to 5 days of photo-oxidative damage (PD)-induced retinal degeneration. Following, retinal function (electroretinography; ERG), morphology (optical coherence tomography; OCT) and measures of cell death (TUNEL) and inflammation (IBA1) were analysed and compared to sedentary controls. To decipher global gene expression changes as a result of voluntary exercise, RNA sequencing and pathway and modular gene co-expression analyses were performed on retinal lysates of exercised and sedentary mice that were subjected to PD, as well as healthy dim-reared controls. Results: Following 5 days of PD, exercised mice had significantly preserved retinal function, integrity and reduced levels of retinal cell death and inflammation, compared to sedentary controls. In response to voluntary exercise, inflammatory and extracellular matrix integrity pathways were significantly modulated, with the gene expression profile of exercised mice more closely trending towards that of a healthy dim-reared retina. Conclusion: We suggest that voluntary exercise may mediate retinal protection by influencing key pathways involved in regulating retinal health and shifting the transcriptomic profile to a healthy phenotype.

Streptococcus makes the cut: Gasdermin A-induced pyroptosis.

The gasdermin family of cell death executor proteins are activated by different proteases under different physiological conditions. A recent study by Deng et al. in Nature revealed that the cysteine protease SpeB from the human pathogen Streptococcus pyogenes directly cleaves and activates Gasdermin A to induce pyroptosis in skin cells.