Inflammatory consequences of inherited disorders affecting neutrophil function

Abstract Primary immunodeficiencies affecting the function of neutrophils and other phagocytic leukocytes are notable for an increased susceptibility to bacterial and fungal infections as a result of impaired leukocyte recruitment, ingestion, and/or killing of microbes. The underlying molecular defects can also impact other innate immune responses to infectious and inflammatory stimuli, leading to inflammatory and autoimmune complications that are not always directly related to infection. This review will provide an update on congenital disorders affecting neutrophil function in which a combination of host defense and inflammatory complications are prominent, including nicotinamide dinucleotide phosphate oxidase defects in chronic granulomatous disease and β2 integrin defects in leukocyte adhesion deficiency.

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The dNTPase activity of SAMHD1 is important for its suppression of innate immune responses in differentiated monocytic cells

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010360 ◽

2019 ◽

Vol 295 (6) ◽

pp. 1575-1586 ◽

Cited By ~ 2

Author(s):

Zhihua Qin ◽

Serena Bonifati ◽

Corine St. Gelais ◽

Tai-Wei Li ◽

Sun-Hee Kim ◽

...

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Nuclear Localization ◽

Sendai Virus ◽

Innate Immune ◽

Type I ◽

Mrna Levels ◽

Innate Immune Responses ◽

Monocytic Cells ◽

Inflammatory Stimuli

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphohydrolase (dNTPase) with a nuclear localization signal (NLS). SAMHD1 suppresses innate immune responses to viral infection and inflammatory stimuli by inhibiting the NF-κB and type I interferon (IFN-I) pathways. However, whether the dNTPase activity and nuclear localization of SAMHD1 are required for its suppression of innate immunity remains unknown. Here, we report that the dNTPase activity, but not nuclear localization of SAMHD1, is important for its suppression of innate immune responses in differentiated monocytic cells. We generated monocytic U937 cell lines stably expressing WT SAMHD1 or mutated variants defective in dNTPase activity (HD/RN) or nuclear localization (mNLS). WT SAMHD1 in differentiated U937 cells significantly inhibited lipopolysaccharide-induced expression of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) mRNAs, as well as IFN-α, IFN-β, and TNF-α mRNA levels induced by Sendai virus infection. In contrast, the HD/RN mutant did not exhibit this inhibition in either U937 or THP-1 cells, indicating that the dNTPase activity of SAMHD1 is important for suppressing NF-κB activation. Of note, in lipopolysaccharide-treated or Sendai virus–infected U937 or THP-1 cells, the mNLS variant reduced TNF-α or IFN-β mRNA expression to a similar extent as did WT SAMHD1, suggesting that SAMHD1-mediated inhibition of innate immune responses is independent of SAMHD1's nuclear localization. Moreover, WT and mutant SAMHD1 similarly interacted with key proteins in NF-κB and IFN-I pathways in cells. This study further defines the role and mechanisms of SAMHD1 in suppressing innate immunity.

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Dual-specificity phosphatase 1: a critical regulator of innate immune responses

Biochemical Society Transactions ◽

10.1042/bst0341018 ◽

2006 ◽

Vol 34 (6) ◽

pp. 1018-1023 ◽

Cited By ~ 95

Author(s):

S.M. Abraham ◽

A.R. Clark

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

P38 Mapk ◽

Time Course ◽

Inflammatory Diseases ◽

Innate Immune ◽

Mitogen Activated Protein Kinase ◽

Innate Immune Responses ◽

Inflammatory Stimuli ◽

Mitogen Activated Protein

Innate immune responses are critically dependent on MAPK (mitogen-activated protein kinase) signalling pathways, in particular JNK (c-Jun N-terminal kinase) and p38 MAPK. Both of these kinases are negatively regulated via their dephosphorylation by DUSP1 (dual-specificity phosphatase 1). Several pro- and anti-inflammatory stimuli converge to regulate the DUSP1 gene and to modulate the time course of its expression. In turn, the pattern of expression of DUSP1 dictates the kinetics of activation of JNK and p38 MAPK, and this influences the expression of several mediators of innate immunity. DUSP1 is therefore a central regulator of innate immunity, and its expression can profoundly affect the outcome of inflammatory challenges. We discuss possible implications for immune-mediated inflammatory diseases and their treatment.

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miR-23a/b suppress cGAS-mediated innate and autoimmunity

Cellular and Molecular Immunology ◽

10.1038/s41423-021-00668-x ◽

2021 ◽

Author(s):

Qiuya Yu ◽

Lei Chu ◽

Yongxing Li ◽

Quanyi Wang ◽

Juanjuan Zhu ◽

...

Keyword(s):

Immune Responses ◽

Autoimmune Diseases ◽

Regulatory Mechanism ◽

Disease Model ◽

Innate Immune ◽

Innate Immune Responses ◽

Simplex Virus ◽

Increased Susceptibility ◽

Hsv 1

AbstractCyclic GMP-AMP synthase (cGAS), a key sensor of intracellular DNA, is essential for eliciting innate immunity against infection, whereas aberrant activation of cGAS by endogenous DNA promotes severe autoimmune diseases. However, it is largely unknown how cGAS expression is regulated during pathogen infection and autoimmunity. Here, we report that during herpes simplex virus type 1 (HSV-1) infection, two microRNAs (miR-23a and miR-23b) whose levels significantly decrease due to their interaction with the lncRNA Oasl2-209 directly regulate the expression of cGAS. Overexpression of miR-23a/b markedly dampens cytosolic DNA-induced innate immune responses, whereas inhibition of miR-23a/b enhances these responses. Mice treated with miR-23a/b agomirs exhibit increased susceptibility to HSV-1 infection. Moreover, cGAS is significantly upregulated in the Trex1−/− mouse autoimmune disease model. Administration of miR-23a/b blunts self DNA-induced autoinflammatory responses in Trex1−/− mice. Collectively, our study not only reveals a novel regulatory mechanism of cGAS expression by miRNAs but also identifies a potential therapy for cGAS-related autoimmune diseases.

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SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1801213115 ◽

2018 ◽

Vol 115 (16) ◽

pp. E3798-E3807 ◽

Cited By ~ 34

Author(s):

Shuliang Chen ◽

Serena Bonifati ◽

Zhihua Qin ◽

Corine St. Gelais ◽

Karthik M. Kodigepalli ◽

...

Keyword(s):

Immune Responses ◽

Viral Infections ◽

Inflammatory Responses ◽

Sendai Virus ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Monocytic Cells ◽

Intracellular Dntp ◽

Inflammatory Stimuli

Sterile alpha motif and HD-domain–containing protein 1 (SAMHD1) blocks replication of retroviruses and certain DNA viruses by reducing the intracellular dNTP pool. SAMHD1 has been suggested to down-regulate IFN and inflammatory responses to viral infections, although the functions and mechanisms of SAMHD1 in modulating innate immunity remain unclear. Here, we show that SAMHD1 suppresses the innate immune responses to viral infections and inflammatory stimuli by inhibiting nuclear factor-κB (NF-κB) activation and type I interferon (IFN-I) induction. Compared with control cells, infection of SAMHD1-silenced human monocytic cells or primary macrophages with Sendai virus (SeV) or HIV-1, or treatment with inflammatory stimuli, induces significantly higher levels of NF-κB activation and IFN-I induction. Exogenous SAMHD1 expression in cells or SAMHD1 reconstitution in knockout cells suppresses NF-κB activation and IFN-I induction by SeV infection or inflammatory stimuli. Mechanistically, SAMHD1 inhibits NF-κB activation by interacting with NF-κB1/2 and reducing phosphorylation of the NF-κB inhibitory protein IκBα. SAMHD1 also interacts with the inhibitor-κB kinase ε (IKKε) and IFN regulatory factor 7 (IRF7), leading to the suppression of the IFN-I induction pathway by reducing IKKε-mediated IRF7 phosphorylation. Interactions of endogenous SAMHD1 with NF-κB and IFN-I pathway proteins were validated in human monocytic cells and primary macrophages. Comparing splenocytes from SAMHD1 knockout and heterozygous mice, we further confirmed SAMHD1-mediated suppression of NF-κB activation, suggesting an evolutionarily conserved property of SAMHD1. Our findings reveal functions of SAMHD1 in down-regulating innate immune responses to viral infections and inflammatory stimuli, highlighting the importance of SAMHD1 in modulating antiviral immunity.

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Intestinal infection results in impaired lung innate immunity to secondary respiratory infection

10.1101/2020.08.03.235457 ◽

2020 ◽

Author(s):

Shubhanshi Trivedi ◽

Allie H. Grossmann ◽

Owen Jensen ◽

Mark J. Cody ◽

Kristi J. Warren ◽

...

Keyword(s):

Immune Responses ◽

Causes Of Death ◽

Neutrophil Extracellular Traps ◽

Innate Immune ◽

Innate Immune Responses ◽

Bacterial Burden ◽

Intestinal Infection ◽

Extracellular Traps ◽

Lung Immunity ◽

Increased Susceptibility

AbstractPneumonia and diarrhea are among the leading causes of death worldwide, and epidemiological studies have demonstrated that diarrhea is associated with an increased risk of subsequent pneumonia. Our aim was to determine the impact of intestinal infection on innate immune responses in the lung. Using a mouse model of intestinal infection by Salmonella enterica serovar Typhimurium (S. Typhimurium), we investigated how infection in the gut compartment can modulate immunity in the lungs and impact susceptibility to bacterial (Klebsiella pneumoniae) challenge. We found alterations in frequencies of innate immune cells in lungs of intestinally-infected mice compared to uninfected mice. On subsequent challenge with K. pneumoniae we found that mice with prior intestinal infection have higher lung bacterial burden and inflammation, increased neutrophil margination, and neutrophil extracellular traps (NETs), but lower overall numbers of neutrophils, compared to mice without prior intestinal infection. Together, these results suggest that intestinal infection impacts lung innate immune responses, most notably neutrophil characteristics, potentially resulting in increased susceptibility to secondary pneumonia.Author summaryInfections of the lung and gut are among the leading causes of death worldwide. Human studies have shown that children with diarrhea are at higher risk of subsequent lung infection. How intestinal infections impact lung immunity is not well known. In the present study, we reveal that bacterial infection of the intestinal mucosa may compromise lung immunity, offering new insights into increased susceptibility to respiratory infections. We found that upon respiratory infection, mice with prior intestinal infection are more moribund and despite having higher bacterial burden, they show reduced numbers of neutrophils in the lung compared to mice without prior intestinal infection. We also found excessive neutrophil extracellular traps formation in the lungs of mice with prior intestinal infection, providing evidence of increased pulmonary tissue damage. Collectively, these data identify a direct link between pulmonary and enteric infection and suggests gut infections impair neutrophils responses in the lungs.

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Chronic ethanol consumption compromises neutrophil function in acute pulmonary Aspergillus fumigatus infection

eLife ◽

10.7554/elife.58855 ◽

2020 ◽

Vol 9 ◽

Author(s):

Nathalia Luisa Sousa de Oliveira Malacco ◽

Jessica Amanda Marques Souza ◽

Flavia Rayssa Braga Martins ◽

Milene Alvarenga Rachid ◽

Janaina Aparecida Simplicio ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Leukocyte Adhesion ◽

Ethanol Consumption ◽

Neutrophil Function ◽

Innate Immune ◽

Chronic Ethanol ◽

New Paradigm ◽

Chronic Ethanol Consumption ◽

Species Production ◽

Increased Susceptibility

Chronic ethanol consumption is a leading cause of mortality worldwide, with higher risks to develop pulmonary infections, including Aspergillus infections. Mechanisms underlying increased susceptibility to infections are poorly understood. Chronic ethanol consumption induced increased mortality rates, higher Aspergillus fumigatus burden and reduced neutrophil recruitment into the airways. Intravital microscopy showed decrease in leukocyte adhesion and rolling after ethanol consumption. Moreover, downregulated neutrophil activation and increased levels of serum CXCL1 in ethanol-fed mice induced internalization of CXCR2 receptor in circulating neutrophils. Bone marrow-derived neutrophils from ethanol-fed mice showed lower fungal clearance and defective reactive oxygen species production. Taken together, results showed that ethanol affects activation, recruitment, phagocytosis and killing functions of neutrophils, causing susceptibility to pulmonary A. fumigatus infection. This study establishes a new paradigm in innate immune response in chronic ethanol consumers.

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GLUT3 as an Intersection of Glycerophospholipid Metabolism and the Innate Immune Response to Candida albicans

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.648988 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xian Wu ◽

Ge Zhang ◽

Wen-Hang Yang ◽

Jing-Tao Cui ◽

Li Zhang ◽

...

Keyword(s):

Immune Response ◽

Candida Albicans ◽

Immune Responses ◽

Innate Immune Response ◽

Glucose Transporter ◽

Regulatory Mechanism ◽

Fungal Infections ◽

Innate Immune ◽

Metabolic Reprogramming ◽

Innate Immune Responses

Immune cells can optimize the management of metabolic resources to balance their energy requirements in order to regulate immune responses. The interconnection between immunometabolism and fungal infections is becoming increasingly apparent. Using proteome and metabolome assays, we found that stimulation of primary human monocytes by Candida albicans was accompanied by upregulation of glucose transporter 3 (GLUT3) and activation of the glycerophospholipid metabolism pathway. Upregulated GLUT3 expression has been preliminarily confirmed in monocytes from patients with C. albicans bloodstream infection. Our findings support the importance of GLUT3 in the complex network of glycerophospholipid metabolism and the innate immune responses against C. albicans. In summary, this study might contribute to decipher the regulatory mechanism between the monocyte metabolic reprogramming and innate immune response and reveal potential targets for the antifungal treatments.

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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