scholarly journals Neutrophil-specific deletion of Syk kinase results in reduced host defense to bacterial infection

Blood ◽  
2009 ◽  
Vol 114 (23) ◽  
pp. 4871-4882 ◽  
Author(s):  
Jessica A. Van Ziffle ◽  
Clifford A. Lowell
Keyword(s):  
Bacterial Infection ◽  
Host Defense ◽  
Myeloid Cells ◽  
Inflammatory Cells ◽  
Defense Responses ◽  
Conditional Knockout ◽  
Neutrophil Extracellular Trap ◽  
Integrin Signaling ◽  
Syk Kinase

Abstract Leukocyte-specific CD18 integrins are critical in mediating cell recruitment and activation during host defense responses to bacterial infection. The signaling pathways downstream of CD18 integrins are dependent on the spleen tyrosine kinase, Syk. To investigate the role integrin signaling plays in host defense, we examined the responses of Syk-deficient neutrophils to bacterial challenge with serum-opsonized Staphylococcus aureus and Escherichia coli. Syk-conditional knockout mice lacking this kinase specifically in myeloid cells or just neutrophils were also used to investigate host responses in vivo. Syk-deficient neutrophils manifested impaired exocytosis of secondary and tertiary granules, reduced cytokine release, and very poor activation of the NADPH oxidase in response to serum-opsonized S aureus and E coli. These functional defects correlated with impaired activation of c-Cbl, Pyk2, Erk1/2, and p38 kinases. Bacterial phagocytosis, neutrophil extracellular trap formation, and killing were also reduced in Syk-deficient cells, with a more profound effect after S aureus challenge. In vivo, loss of Syk in myeloid cells or specifically in neutrophils resulted in reduced clearance of S aureus after subcutaneous or intraperitoneal infection, despite normal recruitment of inflammatory cells. These results indicate that loss of Syk kinase-mediated integrin signaling impairs leukocyte activation, leading to reduced host defense responses.

scholarly journals Ficolins Promote Fungal Clearance in vivo and Modulate the Inflammatory Cytokine Response in Host Defense against Aspergillus fumigatus

2016 ◽  
Vol 8 (6) ◽  
pp. 579-588 ◽  
Author(s):  
Ninette Genster ◽  
Elisabeth Præstekjær Cramer ◽  
Anne Rosbjerg ◽  
Katrine Pilely ◽  
Jack Bernard Cowland ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Host Defense ◽  
Knockout Mice ◽  
Fungal Infections ◽  
Inflammatory Cells ◽  
Lectin Pathway ◽  
Wild Type ◽  
Opportunistic Fungal Pathogen

Aspergillus fumigatus is an opportunistic fungal pathogen that causes severe invasive infections in immunocompromised patients. Innate immunity plays a major role in protection against A. fumigatus. The ficolins are a family of soluble pattern recognition receptors that are capable of activating the lectin pathway of complement. Previous in vitro studies reported that ficolins bind to A. fumigatus, but their part in host defense against fungal infections in vivo is unknown. In this study, we used ficolin-deficient mice to investigate the role of ficolins during lung infection with A. fumigatus. Ficolin knockout mice showed significantly higher fungal loads in the lungs 24 h postinfection compared to wild-type mice. The delayed clearance of A. fumigatus in ficolin knockout mice could not be attributed to a compromised recruitment of inflammatory cells. However, it was revealed that ficolin knockout mice exhibited a decreased production of proinflammatory cytokines in the lungs compared to wild-type mice following A. fumigatus infection. The impaired clearance and cytokine production in ficolin knockout mice was independent of complement, as shown by equivalent levels of A. fumigatus-mediated complement activation in ficolin knockout mice and wild-type mice. In conclusion, this study demonstrates that ficolins are important in initial innate host defense against A. fumigatus infections in vivo.

scholarly journals Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection

2018 ◽  
Vol 215 (4) ◽  
pp. 1035-1045 ◽  
Author(s):  
Sharmila Nair ◽  
Jeremy P. Huynh ◽  
Vicky Lampropoulou ◽  
Ekaterina Loginicheva ◽  
Ekaterina Esaulova ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Conditional Knockout ◽  
Transcriptional Level ◽  
Inhibitory Effects ◽  
Culture Studies ◽  
Inflammatory Conditions ◽  
Neutrophil Depletion ◽  
Species Production

Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1−/− mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1−/−, but not WT, mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1fl/fl, Mrp8-Cre Irg1fl/fl, and CD11c-Cre Irg1fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper Mtb-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail Mtb-induced lung disease.

scholarly journals A novel mouse model of conditional IRAK-M deficiency in myeloid cells: application in lung Pseudomonas aeruginosa infection

2016 ◽  
Vol 23 (2) ◽  
pp. 206-215 ◽  
Author(s):  
Di Jiang ◽  
Jennifer Matsuda ◽  
Reena Berman ◽  
Niccolette Schaefer ◽  
Connor Stevenson ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Mouse Model ◽  
Bacterial Infection ◽  
Knockout Mice ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Conditional Knockout ◽  
Negative Regulator ◽  
Innate Defense

Myeloid cells such as macrophages are critical to innate defense against infection. IL-1 receptor-associated kinase M (IRAK-M) is a negative regulator of TLR signaling during bacterial infection, but the role of myeloid cell IRAK-M in bacterial infection is unclear. Our goal was to generate a novel conditional knockout mouse model to define the role of myeloid cell IRAK-M during bacterial infection. Myeloid cell-specific IRAK-M knockout mice were generated by crossing IRAK-M floxed mice with LysM–Cre knock-in mice. The resulting LysM–Cre+/IRAK-Mfl/wt and control (LysM–Cre–/IRAK-Mfl/wt) mice were intranasally infected with Pseudomonas aeruginosa (PA). IRAK-M deletion, inflammation, myeloperoxidase (MPO) activity and PA load were measured in leukocytes, bronchoalveolar lavage (BAL) fluid and lungs. PA killing assay with BAL fluid was performed to determine mechanisms of IRAK-M-mediated host defense. IRAK-M mRNA and protein levels in alveolar and lung macrophages were significantly reduced in LysM–Cre+/IRAK-Mfl/wt mice compared with control mice. Following PA infection, LysM–Cre+/IRAK-Mfl/wt mice have enhanced lung neutrophilic inflammation, including MPO activity, but reduced PA load. The increased lung MPO activity in LysM–Cre+/IRAK-Mfl/wt mouse BAL fluid reduced PA load. Generation of IRAK-M conditional knockout mice will enable investigators to determine precisely the function of IRAK-M in myeloid cells and other types of cells during infection and inflammation.

scholarly journals JNK2 in myeloid cells impairs insulin’s vasodilator effects in muscle during early obesity development through perivascular adipose tissue dysfunction

2019 ◽  
Vol 317 (2) ◽  
pp. H364-H374
Author(s):  
Rick I. Meijer ◽  
Femke P. M. Hoevenaars ◽  
Erik H. Serné ◽  
John S. Yudkin ◽  
Tom J. A. Kokhuis ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Marrow ◽  
Adipose Tissue ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Inflammatory Cells ◽  
Western Diet ◽  
Perivascular Adipose Tissue ◽  
Muscle Perfusion

Reduced vasodilator properties of insulin in obesity are caused by changes in perivascular adipose tissue and contribute to microvascular dysfunction in skeletal muscle. The causes of this dysfunction are unknown. The effects of a short-term Western diet on JNK2-expressing cells in perivascular adipose tissue (PVAT) on insulin-induced vasodilation and perfusion of skeletal muscle were assessed. In vivo, 2 wk of Western diet (WD) reduced whole body insulin sensitivity and insulin-stimulated muscle perfusion, determined using contrast ultrasonography during the hyperinsulinemic clamp. Ex vivo, WD triggered accumulation of PVAT in skeletal muscle and blunted its ability to facilitate insulin-induced vasodilation. Labeling of myeloid cells with green fluorescent protein identified bone marrow as a source of PVAT in muscle. To study whether JNK2-expressing inflammatory cells from bone marrow were involved, we transplanted JNK2−/− bone marrow to WT mice. Deletion of JNK2 in bone marrow rescued the vasodilator phenotype of PVAT during WD exposure. JNK2 deletion in myeloid cells prevented the WD-induced increase in F4/80 expression. Even though WD and JNK2 deletion resulted in specific changes in gene expression of PVAT; epididymal and subcutaneous adipose tissue; expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, or protein inhibitor of STAT1 was not affected. In conclusion, short-term Western diet triggers infiltration of JNK2-positive myeloid cells into PVAT, resulting in PVAT dysfunction, nonclassical inflammation, and loss of insulin-induced vasodilatation in vivo and ex vivo. NEW & NOTEWORTHY We demonstrate that in the earliest phase of weight gain, changes in perivascular adipose tissue in muscle impair insulin-stimulated muscle perfusion. The hallmark of these changes is infiltration by inflammatory cells. Deletion of JNK2 from the bone marrow restores the function of perivascular adipose tissue to enhance insulin’s vasodilator effects in muscle, showing that the bone marrow contributes to regulation of muscle perfusion.

scholarly journals l-Arginine Synthesis from l-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo

2019 ◽  
Vol 202 (6) ◽  
pp. 1747-1754 ◽  
Author(s):  
Shannon M. Lange ◽  
Melanie C. McKell ◽  
Stephanie M. Schmidt ◽  
Junfang Zhao ◽  
Rebecca R. Crowther ◽  
...  
Keyword(s):  
Host Defense ◽  
Myeloid Cells

scholarly journals Pyk2 Is Required for Neutrophil Degranulation and Host Defense Responses to Bacterial Infection

2010 ◽  
Vol 186 (3) ◽  
pp. 1656-1665 ◽  
Author(s):  
Lynn A. Kamen ◽  
Joseph Schlessinger ◽  
Clifford A. Lowell
Keyword(s):  
Bacterial Infection ◽  
Host Defense ◽  
Defense Responses ◽  
Neutrophil Degranulation

scholarly journals NADPH Oxidase Promotes Neutrophil Extracellular Trap Formation in Pulmonary Aspergillosis

2014 ◽  
Vol 82 (5) ◽  
pp. 1766-1777 ◽  
Author(s):  
Marc Röhm ◽  
Melissa J. Grimm ◽  
Anthony C. D'Auria ◽  
Nikolaos G. Almyroudis ◽  
Brahm H. Segal ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Host Defense ◽  
Ex Vivo ◽  
Critical Role ◽  
Neutrophil Extracellular Trap ◽  
Wild Type ◽  
Content Type ◽  
Bona Fide ◽  
Reactive Oxidant

ABSTRACTNADPH oxidase is a crucial enzyme in antimicrobial host defense and in regulating inflammation. Chronic granulomatous disease (CGD) is an inherited disorder of NADPH oxidase in which phagocytes are defective in generation of reactive oxidant intermediates.Aspergillusspecies are ubiquitous, filamentous fungi, which can cause invasive aspergillosis, a major cause of morbidity and mortality in CGD, reflecting the critical role for NADPH oxidase in antifungal host defense. Activation of NADPH oxidase in neutrophils can be coupled to the release of proteins and chromatin that comingle in neutrophil extracellular traps (NETs), which can augment extracellular antimicrobial host defense. NETosis can be driven by NADPH oxidase-dependent and -independent pathways. We therefore undertook an analysis of whether NADPH oxidase was required for NETosis inAspergillus fumigatuspneumonia. Oropharyngeal instillation of liveAspergillushyphae induced neutrophilic pneumonitis in both wild-type and NADPH oxidase-deficient (p47phox−/−) mice which had resolved in wild-type mice by day 5 but progressed in p47phox−/−mice. NETs, identified by immunostaining, were observed in lungs of wild-type mice but were absent in p47phox−/−mice. Using bona fide NETs and nuclear chromatin decondensation as an early NETosis marker, we found that NETosis required a functional NADPH oxidasein vivoandex vivo. In addition, NADPH oxidase increased the proportion of apoptotic neutrophils. Together, our results show that NADPH oxidase is required for pulmonary clearance ofAspergillushyphae and generation of NETsin vivo. We speculate that dual modulation of NETosis and apoptosis by NADPH oxidase enhances antifungal host defense and promotes resolution of inflammation upon infection clearance.

scholarly journals Bruton’s Tyrosine Kinase-Mediated Signaling in Myeloid Cells Is Required for Protective Innate Immunity During Pneumococcal Pneumonia

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander P. de Porto ◽  
Zhe Liu ◽  
Regina de Beer ◽  
Sandrine Florquin ◽  
Joris J. T. H. Roelofs ◽  
...  
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Host Defense ◽  
Pneumococcal Pneumonia ◽  
Myeloid Cells ◽  
Natural Antibody ◽  
Bruton's Tyrosine Kinase

Bruton’s tyrosine kinase (Btk) is a cytoplasmic kinase expressed in B cells and myeloid cells. It is essential for B cell development and natural antibody-mediated host defense against bacteria in humans and mice, but little is known about the role of Btk in innate host defense in vivo. Previous studies have indicated that lack of (natural) antibodies is paramount for impaired host defense against Streptococcus (S.) pneumoniae in patients and mice with a deficiency in functional Btk. In the present study, we re-examined the role of Btk in B cells and myeloid cells during pneumococcal pneumonia and sepsis in mice. The antibacterial defense of Btk-/- mice was severely impaired during pneumococcal pneumosepsis and restoration of natural antibody production in Btk-/- mice by transgenic expression of Btk specifically in B cells did not suffice to protect against infection. Btk-/- mice with reinforced Btk expression in MhcII+ cells, including B cells, dendritic cells and macrophages, showed improved antibacterial defense as compared to Btk-/- mice. Bacterial outgrowth in Lysmcre-Btkfl/Y mice was unaltered despite a reduced capacity of Btk-deficient alveolar macrophages to respond to pneumococci. Mrp8cre-Btkfl/Y mice with a neutrophil specific paucity in Btk expression, however, demonstrated impaired antibacterial defense. Neutrophils of Mrp8cre-Btkfl/Y mice displayed reduced release of granule content after pulmonary installation of lipoteichoic acid, a gram-positive bacterial cell wall component relevant for pneumococci. Moreover, Btk deficient neutrophils showed impaired degranulation and phagocytosis upon incubation with pneumococci ex vivo. Taken together, the results of our study indicate that besides regulating B cell-mediated immunity, Btk is critical for regulation of myeloid cell-mediated, and particularly neutrophil-mediated, innate host defense against S. pneumoniae in vivo.

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