Depletion of Lipocalin 2 (LCN2) in Mice Leads to Dysbiosis and Persistent Colonization with Segmented Filamentous Bacteria

Lipocalin 2 (LCN2) mediates key roles in innate immune responses. It has affinity for many lipophilic ligands and binds various siderophores, thereby limiting bacterial growth by iron sequestration. Furthermore, LCN2 protects against obesity and metabolic syndrome by interfering with the composition of gut microbiota. Consequently, complete or hepatocyte-specific ablation of the Lcn2 gene is associated with higher susceptibility to bacterial infections. In the present study, we comparatively profiled microbiota in fecal samples of wild type and Lcn2 null mice and show, in contrast to previous reports, that the quantity of DNA in feces of Lcn2 null mice is significantly lower than that in wild type mice (p < 0.001). By using the hypervariable V4 region of the 16S rDNA gene and Next-Generation Sequencing methods, we found a statistically significant change in 16 taxonomic units in Lcn2-/- mice, including eight gender-specific deviations. In particular, members of Clostridium, Escherichia, Helicobacter, Lactococcus, Prevotellaceae_UCG-001 and Staphylococcus appeared to expand in the intestinal tract of knockout mice. Interestingly, the proportion of Escherichia (200-fold) and Staphylococcus (10-fold) as well as the abundance of intestinal bacteria encoding the LCN2-sensitive siderphore enterobactin (entA) was significantly increased in male Lcn2 null mice (743-fold, p < 0.001). This was accompanied by significant higher immune cell infiltration in the ileum as demonstrated by increased immunoreactivity against the pan-leukocyte protein CD45, the lymphocyte transcription factor MUM-1/IRF4, and the macrophage antigen CD68/Macrosialin. In addition, we found a higher expression of mucosal mast cell proteases indicating a higher number of those innate immune cells. Finally, the ileum of Lcn2 null mice displayed a high abundance of segmented filamentous bacteria, which are intimately associated with the mucosal cell layer, provoking epithelial antimicrobial responses and affecting T-helper cell polarization.

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HLA-B27 Transgenic and Wild-Type Rats Display Comparable Inherent Innate Immune Cell-Mediated Antimicrobial Activities That Are Enhanced by the Presence of Colonic Inflammation

Gastroenterology ◽

10.1016/s0016-5085(11)62072-6 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-500-S-501

Author(s):

Michael T. Shanahan ◽

Susan L. Tonkonogy ◽

Ryan B. Sartor

Keyword(s):

Immune Cell ◽

Antimicrobial Activities ◽

Innate Immune ◽

Innate Immune Cell ◽

Hla B27 ◽

Wild Type ◽

Colonic Inflammation

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Innate Immune Effectors in Mycobacterial Infection

Clinical and Developmental Immunology ◽

10.1155/2011/347594 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 55

Author(s):

Hiroyuki Saiga ◽

Yosuke Shimada ◽

Kiyoshi Takeda

Keyword(s):

Immune Responses ◽

Bacterial Infections ◽

Mycobacterial Infection ◽

Innate Immune ◽

Pathogenic Microorganisms ◽

Lipocalin 2 ◽

Innate Immune Responses ◽

Active Vitamin ◽

Lectin Receptors ◽

Adaptive Immune

Tuberculosis, which is caused by infection withMycobacterium tuberculosis(Mtb), remains one of the major bacterial infections worldwide. Host defense against Mtb is mediated by a combination of innate and adaptive immune responses. In the last 15 years, the mechanisms for activation of innate immunity have been elucidated. Toll-like receptors (TLRs) have been revealed to be critical for the recognition of pathogenic microorganisms including mycobacteria. Subsequent studies further revealed that NOD-like receptors and C-type lectin receptors are responsible for the TLR-independent recognition of mycobacteria. Several molecules, such as active vitamin D3, secretary leukocyte protease inhibitor, and lipocalin 2, all of which are induced by TLR stimulation, have been shown to direct innate immune responses to mycobacteria. In addition, Irgm1-dependent autophagy has recently been demonstrated to eliminate intracellular mycobacteria. Thus, our understanding of the mechanisms for the innate immune response to mycobacteria is developing.

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Changes in the microbiota cause genetically modified Anopheles to spread in a population

Science ◽

10.1126/science.aak9691 ◽

2017 ◽

Vol 357 (6358) ◽

pp. 1396-1399 ◽

Cited By ~ 30

Author(s):

Andrew Pike ◽

Yuemei Dong ◽

Nahid Borhani Dizaji ◽

Anthony Gacita ◽

Emmanuel F. Mongodin ◽

...

Keyword(s):

Immune System ◽

Innate Immune System ◽

Bacterial Infections ◽

Genetically Modified ◽

Reproductive Organs ◽

Innate Immune ◽

Wild Type ◽

Immune Genes ◽

Cage Population ◽

Genetically Modified Mosquitoes

The mosquito’s innate immune system controls both Plasmodium and bacterial infections. We investigated the competitiveness of mosquitoes genetically modified to alter expression of their own anti-Plasmodium immune genes in a mixed-cage population with wild-type mosquitoes. We observed that genetically modified mosquitoes with increased immune activity in the midgut tissue did not have an observed fitness disadvantage and showed reduced microbial loads in both the midgut and reproductive organs. These changes result in a mating preference of genetically modified males for wild-type females, whereas wild-type males prefer genetically modified females. These changes foster the spread of the genetic modification in a mosquito cage population.

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Immunoregulatory networks in sickle cell alloimmunization

Hematology ◽

10.1182/asheducation-2016.1.457 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 457-461 ◽

Cited By ~ 7

Author(s):

Karina Yazdanbakhsh

Keyword(s):

T Cells ◽

Sickle Cell ◽

Immune Cell ◽

Cell Polarization ◽

Innate Immune ◽

Future Design ◽

Cell Responses ◽

Treatment And Prevention ◽

Follicular Helper ◽

Free Heme

Abstract Red blood cell (RBC) transfusions are critical for treatment and prevention of complications of sickle cell disease (SCD), and most SCD patients will receive 1 or more transfusions by age 20. However, SCD alloimmunization remains a serious complication of transfusions that can lead to life-threatening acute and delayed transfusion reactions. Alloimmunization rates are higher in SCD patients most likely due to RBC antigenic differences between largely white donors vs mainly African-American recipients and frequency of transfusions. However, it remains unclear why some but not all SCD patients develop alloantibodies. Cellular immune responses that differ between alloimmunized and nonalloimmunized SCD patients are beginning to be characterized. Altered CD4+ T helper cell responses, known to control immunoglobulin G production, have been identified in alloimmunized SCD patients, including abnormalities in regulatory T cells, as well as helper type 1 (TH1), TH17, and follicular helper T cells. Furthermore, heightened innate immune cell responses to cell free heme with cell polarization toward proinflammatory T cell profiles were recently reported in SCD antibody responders, suggesting that the ongoing hemolytic state in SCD may impair the ability of innate immune cells in these already alloimmunized patients to counter alloimmunization. Identification of molecular pathways in key cellular components that differ between alloimmunized and nonalloimmunized SCD patients is likely to lead to identification of biomarkers of alloimmunization and future design of targeted therapies to prevent or even dampen alloantibody responses in these highly susceptible patients.

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mTORC1-Activated Monocytes Increase Tregs and Inhibit the Immune Response to Bacterial Infections

Mediators of Inflammation ◽

10.1155/2016/7369351 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Lijun Fang ◽

Huaijun Tu ◽

Wei Guo ◽

Shixuan Wang ◽

Ting Xue ◽

...

Keyword(s):

Immune Response ◽

Bacterial Infections ◽

Immune Cell ◽

Critical Role ◽

Innate Immune ◽

E Coli ◽

Upstream Regulator ◽

Mtorc1 Signaling ◽

Activated Monocytes ◽

Mtorc1 Activation

The TSC1/2 heterodimer, a key upstream regulator of the mTOR, can inhibit the activation of mTOR, which plays a critical role in immune responses after bacterial infections. Monocytes are an innate immune cell type that have been shown to be involved in bacteremia. However, how the mTOR pathway is involved in the regulation of monocytes is largely unknown. In our study, TSC1 KO mice and WT mice were infected withE. coli. When compared to WT mice, we found higher mortality, greater numbers of bacteria, decreased expression of coactivators in monocytes, increased numbers of Tregs, and decreased numbers of effector T cells in TSC1 KO mice. Monocytes obtained from TSC1 KO mice produced more ROS, IL-6, IL-10, and TGF-βand less IL-1, IFN-γ, and TNF-α. Taken together, our results suggest that the inhibited immune functioning in TSC1 KO mice is influenced by mTORC1 activation in monocytes. The reduced expression of coactivators resulted in inhibited effector T cell proliferation. mTORC1-activated monocytes are harmful during bacterial infections. Therefore, inhibiting mTORC1 signaling through rapamycin administration could rescue the harmful aspects of an overactive immune response, and this knowledge provides a new direction for clinical therapy.

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Inflammation-induced alterations in maternal-fetal Heme Oxygenase (HO) are associated with sustained innate immune cell dysregulation in mouse offspring

PLoS ONE ◽

10.1371/journal.pone.0252642 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252642

Author(s):

Maide Ozen ◽

Hui Zhao ◽

Flora Kalish ◽

Yang Yang ◽

Lauren L. Jantzie ◽

...

Keyword(s):

Heme Oxygenase ◽

Immune Cell ◽

Fetal Liver ◽

Innate Immune ◽

Innate Immune Cell ◽

Cell Populations ◽

Heme Oxygenase 1 ◽

Wild Type ◽

Evolutionarily Conserved ◽

Young Adolescence

Heme oxygenase-1 (HO-1) is an evolutionarily conserved stress response enzyme and important in pregnancy maintenance, fetal and neonatal outcomes, and a variety of pathologic conditions. Here, we investigated the effects of an exposure to systemic inflammation late in gestation [embryonic day (E)15.5] on wild-type (Wt) and HO-1 heterozygous (Het, HO-1+/-) mothers, fetuses, and offspring. We show that alterations in fetal liver and spleen HO homeostasis during inflammation late in gestation can lead to a sustained dysregulation of innate immune cell populations and intracellular myeloid HO-1 expression in the spleen through young adolescence [postnatal day 25] in mice.

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New Insights into the Antimicrobial Effect of Mast Cells against Enterococcus faecalis

Infection and Immunity ◽

10.1128/iai.02114-14 ◽

2014 ◽

Vol 82 (11) ◽

pp. 4496-4507 ◽

Cited By ~ 18

Author(s):

Matthias Scheb-Wetzel ◽

Manfred Rohde ◽

Alicia Bravo ◽

Oliver Goldmann

Keyword(s):

Mast Cells ◽

Enterococcus Faecalis ◽

Bacterial Infections ◽

Immune Cell ◽

Hospital Setting ◽

Antimicrobial Effect ◽

Innate Immune ◽

Immune Cell Population ◽

Necrosis Factor Alpha ◽

Content Type

ABSTRACTEnterococcus faecalishas emerged as an important cause of life-threatening multidrug-resistant bacterial infections in the hospital setting. The pathogenesis of enterococcal infections has remained a relatively neglected field despite their obvious clinical relevance. The objective of this study was to characterize the interactions between mast cells (MCs), an innate immune cell population abundant in the intestinal lamina propria, andE. faecalis. This study was conducted with primary bone marrow-derived murine MCs. The results demonstrated that MCs exerted an antimicrobial effect againstE. faecalisthat was mediated both by degranulation, with the concomitant discharge of the antimicrobial effectors contained in the granules, and by the release of extracellular traps, in whichE. faecaliswas snared and killed. In particular, the cathelicidin LL-37 released by the MCs had potent antimicrobial effect againstE. faecalis. We also investigated the specific receptors involved in the recognition ofE. faecalisby MCs. We found that Toll-like receptors (TLRs) are critically involved in the MC recognition ofE. faecalis, since MCs deficient in the expression of MyD88, an adaptor molecule required for signaling by most TLRs, were significantly impaired in their capacity to degranulate, to reduceE. faecalisgrowth as well as to release tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) after encountering this pathogen. Furthermore, TLR2 was identified as the most prominent TLR involved in the recognition ofE. faecalisby MCs. The results of this study indicate that MCs may be important contributors to the host innate immune defenses againstE. faecalis.

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