The All-Encompassing Importance of Innate Immunity

In their AAI President’s Addresses reproduced in this issue, Jeremy M. Boss, Ph.D. (AAI ’94; AAI President 2019-2020) and Jenny P.-Y. Ting, Ph.D. (AAI ’97; AAI President 2020-2021) welcomed attendees to the AAI annual meeting, Virtual IMMUNOLOGY2021. Due to the SARS-CoV-2 pandemic and the cancellation of IMMUNOLOGY2020, Dr. Boss and Dr. Ting each presented their respective President’s Address to open the meeting

Holding the inflammatory system in check: NLRs keep it cool

Inflammation is a double-edged sword. While short-lived, acute inflammation is essential for the repair and resolution of infection and damage, uncontrolled and unresolved chronic inflammation is central to several diseases, including cancer, autoimmune diseases, allergy, metabolic disease, and cardiovascular disease. This report aims to review the literature regarding several members of the nucleotide-binding domain, leucine-rich repeat-containing receptor (NLR) family of pattern recognition sensors/receptors that serve as checkpoints for inflammation. Understanding the negative regulation of inflammation is highly relevant to the development of therapeutics for inflammatory as well as infectious diseases

The pathogenic role of the inflammasome in neurodegenerative diseases

The inflammasome is a large macromolecular complex that contains multiple copies of a receptor or sensor of pathogen-derived or damage-derived molecular patterns, pro-caspase-1, and an adaptor called ASC (apoptotic speck containing protein with a CARD), which results in caspase-1 maturation. Caspase-1 then mediates the release of pro-inflammatory cytokines such as IL-1β and IL-18. These cytokines play critical roles in mediating immune responses during inflammation and innate immunity. Broader studies of the inflammasome over the years have implicated their roles in the pathogenesis of a variety of inflammatory diseases. Recently, studies have shown that the inflammasome modulates neuroinflammatory cells and the initial stages of neuroinflammation. A secondary cascade of events associated with neuroinflammation (such as oxidative stress) has been shown to activate the inflammasome, making the inflammasome a promising therapeutic target in the modulation of neurodegenerative diseases. This review will focus on the pathogenic role that inflammasomes play in neurologic diseases such as Alzheimer's disease, traumatic brain injury, and multiple sclerosis

NLRs and the dangers of pollution and aging

Inflammatory interleukin 1β production after silica and alum crystal or β-amyloid uptake occurs via a process involving lysosomal destabilization and release of cathepsin B that activates the NALP3 inflammasome

Differential regulation of cytokine-induced major histocompatibility complex class II expression and nitric oxide release in rat microglia and astrocytes by effectors of tyrosine kinase, protein kinase C, and cAMP

Two glial cell populations of the CNS, astrocytes and microglia, were examined for expression of two immunologically important molecules, MHC class II and nitric oxide (NO), following treatment with cytokines. IFN-γ induced both molecules in microglia at substantially higher levels than astrocytes. The addition of TNF-α to IFN-γ elevated class II expression and NO in both cells. Genistein, an inhibitor of tyrosine kinases, and calphostin, an inhibitor of protein kinase C, diminished cytokine induction of class II MHC and NO in both glial populations. Forskolin was most effective in inhibiting class II MHC expression, but had little inhibitory effect on NO production. These results indicate microglia are more effective than astrocytes in producing cell-associated and secreted immune mediators in response to IFN-γ and or TNF-α and multiple parallel, but distinct, signaling events are required for cytokine induced class II MHC or NO production

Mitochondrial GSDMD Pores DAMPen Pyroptosis

Noncanoncial inflammasome activation by cytosolic lipopolysaccharide (LPS) causes pyroptotic cell death facilitated by gasdermin D (GSDMD) pore formation. In this issue of Immunity, Huang et al. describe how cytosolic LPS in endothelial cells does not cause cell death but restrains endothelial cell proliferation. © 2020 Elsevier Inc.Noncanoncial inflammasome activation by cytosolic lipopolysaccharide (LPS) causes pyroptotic cell death facilitated by gasdermin D (GSDMD) pore formation. In this issue of Immunity, Huang et al. describe how cytosolic LPS in endothelial cells does not cause cell death but restrains endothelial cell proliferation

A spike in inflammation

The innate immune system is the first line of defence against invading microorganisms. Specialized immune cells, primarily myeloid cells, sense conserved pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs) to coordinate an immune response. One important class of PRRs is the nucleotide-binding domain and leucine-rich-repeat (NLR) proteins. In the presence of pathogens, NLR proteins trigger the formation of the inflammasome. This large macromolecular complex has caspase-1 activity, which stimulates production of the inflammatory cytokines interleukin (IL)-1β and IL-18, leading to inflammation and inflammatory cell death (pyroptosis). Extensive work has characterized the biochemical cues that activate immunity through PRRs such as NLRs. However, in addition to conserved molecular patterns, pathogens also adopt conserved shapes and surface structures. For example, some bacteria have complex surface topographies created through nanofeatures such as flagella, pili and fimbriae. It has long been hypothesized that these physical cues are also sensed by the immune system through PRRs, but definitive experimental proof has remained elusive, partly because of the difficulties in separating the physical and biochemical immunological inputs produced by these natural structures

Comparison and quantitation of Ia antigen expression on cultured macroglia and ameboid microglia from Lewis rat cerebral cortex: analyses and implications

We isolated two subclasses of astrocytes, oligodendrocytes and ameboid microglia from Lewis rat cerebral cortex and analyzed Ia antigen expression on each glial cell type by immunofluorescent microscopy and cytofluorometry. All of these expressed little or no Ia without interferon-γ (IFN-γ) treatment. Following IFN-γ treatment, Ia expression was observed on a majority (∼ 80%) of ameboid microglia, on half (∼ 55%) of the type 1 astrocytes, on a small number (∼ 7%) of type 2 astrocytes, but not on oligodendrocytes. These findings suggest that the type 1 astrocyte and microglia may play more predominant roles in Ia-related, immune-mediated intracerebral lesions although the type 2 astrocytes may also be involved

Convergence of Targeted and Immune Therapies for the Treatment of Oncogene-Driven Cancers

Summary: In this issue, Hattori and colleagues capitalized on targeted small-molecule covalent inhibitors of one KRAS mutant with a G12C substitution and of other oncoproteins to create drug–peptide conjugates that serve as cancer neoantigens that prompt an immune response to oncogene-mutant cancer cells. This immunotherapy strategy can serve as an effective approach to overcome the treatment-induced resistance that limits the effectiveness of essentially all small molecule–based targeted anticancer drugs

Differential suppression of interferon-γ-induced Ia antigen expression on cultured rat astroglia and microglia by second messengers

The roles of intracellular second messengers in interferon-γ (IFN-γ)-induced Ia antigen (Ag) expression by astroglia and microglia were examined. Ia Ag on both glia types was induced by IFN-γ. Reagents known to increase intracellular cAMP or activate intracellular protein kinase C (PKC) reduced IFN-γ-induced Ia Ag expression by astroglia. In contrast, increasing intracellular cAMP had no suppressive effect on Ia Ag expression by microglia. These results indicate (1) cAMP and PKC negatively regulate IFN-γ-induced Ia expression on astroglia, and (2) Ia expression is regulated differentially in astroglia vs. microglia. These findings may explain the frequent observation of Ia+ microglia (or macrophages) but not astroglia in various neurodegenerative diseases