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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2014)
Type 2 innate lymphoid cells (ILC2) are a novel population of innate lymphocytes lacking expression of lineage markers. ILC2 lack antigen specificity and are instead activated by epithelial cytokines IL-33 and IL-25. Similar to type 2 T helper cells, ILC2 produce IL-5 and IL-13, two cytokines shown to be important in the development and pathology of asthma. Cysteinyl leukotrienes are important inflammatory mediators and potent bronchoconstrictors derived from arachidonic acid. 5-lipoxygenase converts arachidonic acid into leukotriene A4 (LTA4) and LTC4 synthase subsequently generates the cysteinyl leukotrienes, LTC4, LTD4, and LTE4. Expression of the cysteinyl leukotriene receptor 1 (CysLT1R) on ILC2 was shown both by flow cytometric analysis and PCR of sorted ILC2. Leukotriene C4, D4, and E4 administered intranasally induced ILC2 activation in vivo, and leukotriene D4 induced ILC2 IL-4, IL-5, and IL-13 production in vitro. Here, we show that the cysteinyl leukotrienes play a role as regulators and activators of type 2 innate lymphoid cells apart from known roles in bronchoconstriction and activation of other inflammatory cells
    Cover page: Type 2 Innate Lymphoid Cell Activation by Cysteinyl Leukotrienes : : a Novel Mechanism of Lipid-Mediated Allergic Inflammation
    • Thesis
    • Peer Reviewed
    UC San Diego Electronic Theses and Dissertations (2020)

    Streptococcus agalactiae (Group B Streptococcus, GBS) is the most common neonatal

    pathogen capable of causing devastating disease in newborns, yet healthy adults are largely

    unaffected. The cellular and molecular mechanisms for neonatal susceptibility to GBS

    pneumonia and sepsis are incompletely understood. Here we optimized a mouse model of

    GBS pneumonia to test the role of alveolar macrophage (AM) maturation in host

    vulnerability to severe disease. Compared with juvenile and adult mice, neonatal mice

    infected with GBS had increased mortality and persistence of lung injury. In addition,

    neonatal mice were defective in GBS phagocytosis and killing. AM depletion and disruption

    of AM differentiation in Csf2-/- mice both impaired GBS clearance. AM engage the heavily

    sialylated GBS capsule via the cell surface Siglec receptors Sialoadhesin (Sn) and Siglec-E.

    Newborn AM expressed significantly lower levels of Sn, although both newborn and adult

    AM expressed Siglec-E. Sn is exclusively expressed by CD11b lo and CD11b hi AM, while

    Siglec-E is more commonly expressed by lung myeloid cells. AM Sn expression decreased

    after GBS infection in both adults and neonates, this decrease seemed to be mediated by the

    GBS Sia-Siglec-E ligation. The GBS Sia mutant, neuA, failed to decrease Sn expression in

    either adults or neonates. Cell surface protein expression of Sn also decreased at 24 h after

    GBS infection in the WT neonates, however, Sig-E-/- neonates maintained surface expression

    of Sn at 24 h of infection. We propose that a developmental delay in Sn expression on AM

    may prevent effective killing and clearing of GBS from the newborn lung. Next we

    investigated the impact host Sia could have on AM development and responsiveness to

    infection. While the fetal lung lacks expression of 2-3 Sia in the lung, the major sialylated

    glycoprotein in the urine, Tamm-Horsfall Protein (THP), was found in the fetal lung. THP-/-

    neonates, at PND1, 2, and 8 all showed decreased expression of Siglec-E, and higher

    expression of Siglec-F at PND2. We hypothesize that the developing fetus aspirates amniotic

    fluid, of which a major component is fetal urine containing THP, into the lung during

    gestation bringing a source of Sia into the lungs and regulates fetal AM development and

    suppresses inflammatory activity.

      Cover page: Developmental Immaturity of Siglec Receptor Expression on Neonatal Alveolar Macrophages Predisposes to Severe Group B Streptococcal Infection
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