Alveolar macrophages (AMs) express the class A scavenger receptor macrophage receptor with collagenous structure (MARCO), but its role in vivo in lung defense against bacteria and environmental particles has not been studied. We used MARCO-deficient mice to directly test the in vivo role of AM MARCO in innate defense against pneumococcal infection and environmental particles. In a murine model of pneumococcal pneumonia, MARCO−/− mice displayed an impaired ability to clear bacteria from the lungs, increased pulmonary inflammation and cytokine release, and diminished survival. In vitro binding of Streptococcus pneumoniae and in vivo uptake of unopsonized particles by MARCO−/− AMs were dramatically impaired. MARCO−/− mice treated with the “inert” environmental particle TiO2 showed enhanced inflammation and chemokine expression, indicating that MARCO-mediated clearance of inert particles by AMs prevents inflammatory responses otherwise initiated by other lung cells. Our findings point to an important role of MARCO in mounting an efficient and appropriately regulated innate immune response against inhaled particles and airborne pathogens.

Maternal asthma is a risk factor for development of asthma in children, but mechanisms remain unclear. Offspring of asthmatic mother mice (sensitized and repeatedly exposed to OVA Ag) showed airway hyperresponsiveness and allergic pulmonary inflammation after an intentionally suboptimal OVA sensitization and exposure protocol that had little effect on normal offspring. Similar results were obtained when offspring of OVA-allergic mothers were exposed to an unrelated allergen, casein, indicating that the maternal effect is allergen independent and not transferred by OVA-specific Abs. Premating treatment with neutralizing anti-IL-4 Ab or reduction of maternal allergen exposure abrogated the maternal effect, showing a critical mechanistic role for IL-4 and suggesting an additional benefit of allergen avoidance.

Alveolar macrophages (AMs) avidly bind and ingest inhaled environmental particles and bacteria. To identify the particle binding receptor(s) on human AMs, we used functional screening of anti-human AM hybridomas and isolated a mAb, PLK-1, which inhibits AM binding of unopsonized particles (e.g., TiO2, latex beads; 63 ± 5 and 67 ± 4% inhibition, respectively, measured by flow cytometry; n = 11) and unopsonized bacteria (∼84 and 41% inhibition of Escherichia coli and Staphylococcus aureus binding by mAb PLK-1, respectively). The PLK-1 Ag was identified as the human class A scavenger receptor (SR) MARCO (macrophage receptor with collagenous structure) by observing specific immunolabeling of COS cells transfected with human MARCO (but not SR-AI/II) cDNA and by immunoprecipitation by PLK-1 of a protein of appropriate molecular mass (∼70 kDa) from both normal human bronchoalveolar lavage cells (>90% AMs) and human MARCO-transfected COS cells. PLK-1 also specifically inhibited particle binding by COS cells, only after transfection with human MARCO cDNA. Immunostaining showed specific labeling of AMs within human lung tissue, bronchoalveolar lavage samples, as well as macrophages in other sites (e.g., lymph node and liver). Using COS transfectants with different truncated forms of MARCO, allowed epitope mapping for the PLK-1 Ab to MARCO domain V between amino acid residues 420 and 431. A panel of Abs to various SRs identified expression on AMs, but failed to inhibit TiO2 or S. aureus binding. The data support a dominant role for MARCO in the human AM defense against inhaled particles and pathogens.

Mammalian oocytes are arrested at the prophase of meiosis I during fetal or postnatal development, and the meiosis is resumed by the preovulatory surge of luteinizing hormone. The in vivo functional roles of cyclin-dependent kinases (Cdks) during the resumption of meiosis in mammalian oocytes are largely unknown. Previous studies have shown that deletions of Cdk3, Cdk4 or Cdk6 in mice result in viable animals with normal oocyte maturation, indicating that these Cdks are not essential for the meiotic maturation of oocytes. In addition, conventional knockout of Cdk1 and Cdk2 leads to embryonic lethality and postnatal follicular depletion, respectively, making it impossible to study the functions of Cdk1 and Cdk2 in oocyte meiosis. In this study, we generated conditional knockout mice with oocyte-specific deletions of Cdk1 and Cdk2. We showed that the lack of Cdk1, but not of Cdk2, leads to female infertility due to a failure of the resumption of meiosis in the oocyte. Re-introduction of Cdk1 mRNA into Cdk1-null oocytes largely resumed meiosis. Thus, Cdk1 is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes. We also found that Cdk1 maintains the phosphorylation status of protein phosphatase 1 and lamin A/C in oocytes in order for meiosis resumption to occur.

In this study we assessed the in vitro toxicity of 14 paired indoor and outdoor PM(2.5) samples (particulate matter < or =2.5 microm in aerodynamic diameter) collected in 9 Boston-area homes. Samples were collected as part of a large indoor particle characterization study that included the simultaneous measurement of indoor and outdoor PM(2.5), particle size distributions, and compositional data (e.g., elemental/organic carbon, endotoxin, etc.). Bioassays were conducted using rat alveolar macrophages (AMs), and tumor necrosis factor (TNF) was measured to assess particle-induced proinflammatory responses. Additional experiments were also conducted in which AMs were primed with lipopolysaccharides (LPS) to simulate preexisting pulmonary inflammation such as that which might exist in sick and elderly individuals. Significant TNF production above that of negative controls was observed for AMs exposed to either indoor or outdoor PM(2.5). TNF releases were further amplified for primed AMs, suggesting that preexisting inflammation can potentially exacerbate the toxicity of not only outdoor PM(2.5) (as shown by previous studies) but also indoor PM(2.5). In addition, indoor particle TNF production was found to be significantly higher than outdoor particle TNF production in unprimed AMs, both before and after normalization for endotoxin concentrations. Our results suggest that indoor-generated particles may be more bioactive than ambient particles. Endotoxin was demonstrated to mediate proinflammatory responses for both indoor and outdoor PM(2.5), but study findings suggest the presence of other proinflammatory components of fine particles, particularly for indoor-generated particles. Given these study findings and the fact that people spend 85-90% of their time indoors, future studies are needed to address the toxicity of indoor particles.

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Given the fact that people spend 85-90% of their time indoors (1), it is widely recognized that a significant portion of total personal exposures to particulate matter (PM) occurs in indoor environments. Indoor particles are composed of both ambient particles, which infiltrate indoors, and nonambient particles, which are generated indoors during the daily activities of home occupants. In a previous paper (2), we demonstrated that indoor fine particle concentrations in nine Boston-area study homes were significantly elevated during cooking, cleaning, and other general indoor activities involving combustion (e.g., burning candles) or physical movement (e.g., walking). Indoor source events were typically of short duration, but many were of very high intensity, capable of raising hourly concentrations of PM 2.5 (particulate matter ≤ 2.5 µm in aerodynamic diameter) by tens to hundreds of micrograms per cubic meter. Furthermore, this and other studies have shown that indoor particle events can substantially modify the size distribution and composition of indoor particles (2-7). Exposures to indoor-generated particles may be highly relevant to public health because of the high frequency of exposure to large short-term events.

Congenital heart disease (CHD) poses a significant global health and economic burden—despite advances in treating CHD reducing the mortality risk, globally CHD accounts for approximately 300,000 deaths yearly. Children with CHD experience both acute and chronic cardiac complications, and though treatment options have improved, some remain extremely invasive. A challenge in addressing these morbidity and mortality risks is that little is known regarding the cause of many CHDs and current evidence suggests a multifactorial etiology. Some studies implicate an immune contribution to CHD development; however, the role of the immune system is not well-understood. Defining the role of the immune and inflammatory responses in CHD therefore holds promise in elucidating mechanisms underlying these disorders and improving upon current diagnostic and treatment options. In this review, we address the current knowledge coinciding CHDs with immune and inflammatory associations, emphasizing conditions where this understanding would provide clinical benefit, and challenges in studying these mechanisms.