Macrophages have been found in virtually all organs and tissues of the body. Within the lung, macrophages exist in distinct compartments, such as the lung interstitium, and within the airspace. Lung ...macrophages exhibit a variety of functions that depend on their ontogeny and tissue location. Airspace macrophages are sentinel cells located at the interface between the external and internal environments and are critical for tissue homeostasis, protection from pathogens, and clearance of dead cells and debris. In addition to these protective roles, airspace macrophages also generate inflammation and can drive tissue injury and repair processes resulting in fibrosis and emphysema. The diverse functional roles of airspace macrophages within the human lung is an area of active research. Recent events have demonstrated that some individuals are uniquely susceptible to different injuries or disease states. Here, what is "normal" when examining myeloid cells in human airways is discussed.
Although IL-9 has potent anti-tumor activity in adoptive cell transfer therapy, some models suggest that it can promote tumor growth. Here, we show that IL-9 signaling is associated with poor ...outcomes in patients with various forms of lung cancer, and is required for lung tumor growth in multiple mouse models. CD4
T cell-derived IL-9 promotes the expansion of both CD11c
and CD11c
interstitial macrophage populations in lung tumor models. Mechanistically, the IL-9/macrophage axis requires arginase 1 (Arg1) to mediate tumor growth. Indeed, adoptive transfer of Arg1
but not Arg1
lung macrophages to Il9r
mice promotes tumor growth. Moreover, targeting IL-9 signaling using macrophage-specific nanoparticles restricts lung tumor growth in mice. Lastly, elevated expression of IL-9R and Arg1 in tumor lesions is associated with poor prognosis in lung cancer patients. Thus, our study suggests the IL-9/macrophage/Arg1 axis is a potential therapeutic target for lung cancer therapy.
According to this work, expression of Grp is not affected by IL-17A blockade, but expression of the receptor is diminished.The Grpr gene is located on the X chromosome, as the authors point out in ...their discussion....study is needed to investigate the applicability of these findings to males.By the same token, ozone-induced lung-function decrements are greater in obese women than in obese men (12), and increased body mass index is predictive of asthma incidence in women, but not in men (13)....a comparison between male and female Grpr responses to ozone in the context of obesity would be informative regardless of the outcome....one should caution that the role of obesity in lung inflammation is complex.
In the coronavirus disease 2019 era, biocidal products are increasingly used for controlling harmful organisms, including microorganisms. However, assuring safety against adverse health effects is a ...critical issue from a public health standpoint. This study aimed to provide an overview of key aspects of risk assessment, management, and communication that ensure the safety of biocidal active ingredients and products. The inherent characteristics of biocidal products make them effective against pests and pathogens; however, they also possess potential toxicities. Therefore, public awareness regarding both the beneficial and potential adverse effects of biocidal products needs to be increased. Biocidal active ingredients and products are regulated under specific laws: the Federal Insecticide, Fungicide, and Rodenticide Act for the United States; the European Union (EU) Biocidal Products Regulation for the EU; and the Consumer Chemical Products and Biocide Safety Management Act for the Republic of Korea. Risk management also needs to consider the evidence of enhanced sensitivity to toxicities in individuals with chronic diseases, given the increased prevalence of these conditions in the population. This is particularly important for post‐marketing safety assessments of biocidal products. Risk communication conveys information, including potential risks and risk‐reduction measures, aimed at managing or controlling health or environmental risks. Taken together, the collaborative effort of stakeholders in risk assessment, management, and communication strategies is critical to ensuring the safety of biocidal products sold in the market as these strategies are constantly evolving.
Despite recent advances in understanding macrophage activation, little is known regarding how human alveolar macrophages in health calibrate its transcriptional response to canonical TLR4 activation. ...In this study, we examined the full spectrum of LPS activation and determined whether the transcriptomic profile of human alveolar macrophages is distinguished by a TIR-domain-containing adapter-inducing interferon-β (TRIF)-dominant type I interferon signature. Bronchoalveolar lavage macrophages were obtained from healthy volunteers, stimulated in the presence or absence of ultrapure LPS in vitro, and whole transcriptomic profiling was performed by RNA sequencing (RNA-Seq). LPS induced a robust type I interferon transcriptional response and Ingenuity Pathway Analysis predicted interferon regulatory factor (IRF)7 as the top upstream regulator of 89 known gene targets. Ubiquitin-specific peptidase (USP)-18, a negative regulator of interferon α/β responses, was among the top up-regulated genes in addition to IL10 and USP41, a novel gene with no known biological function but with high sequence homology to USP18. We determined whether IRF-7 and USP-18 can influence downstream macrophage effector cytokine production such as IL-10. We show that IRF-7 siRNA knockdown enhanced LPS-induced IL-10 production in human monocyte-derived macrophages, and USP-18 overexpression attenuated LPS-induced production of IL-10 in RAW264.7 cells. Quantitative PCR confirmed upregulation of USP18, USP41, IL10, and IRF7. An independent cohort confirmed LPS induction of USP41 and IL10 genes. These results suggest that IRF-7 and predicted downstream target USP18, both elements of a type I interferon gene signature identified by RNA-Seq, may serve to fine-tune early cytokine response by calibrating IL-10 production in human alveolar macrophages.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Accurate and reproducible assessments of experimental lung injury and inflammation are critical for basic and translational research. In particular, investigators use various methods for BAL and ...euthanasia; however, the impact of these methods on assessments of injury and inflammation is unknown. To define potential effects, we compared methods of lavage and euthanasia in uninjured mice and after a mild lung injury model (ozone). C57BL/6J male mice (8-10 weeks old) underwent BAL after euthanasia with ketamine/xylazine, carbon dioxide (CO
), or isoflurane. BAL methods included 800 μl of isotonic solution instilled and withdrawn three times, and one or three passive fills and drainage to 20 cm H
O. Parallel experiments were performed 24 hours after 3 hours of ozone (O
) exposure at 2 ppm. BAL total cell counts/differentials and total protein/albumin were determined. Lung histology was evaluated for lung inflammation or injury. BAL cells were cultured and stimulated with PBS, PMA, or LPS for 4 hours and supernatants were evaluated for cytokine content. In uninjured mice, we observed differences due to the lavage and euthanasia methods used. The lavage method increased total cells and total protein/albumin in uninjured and O
-exposed mice, with the 800-μl instillation having the highest values. Isoflurane increased total BAL cells, whereas CO
euthanasia increased the total protein/albumin levels in uninjured mice. These effects limited our ability to detect differences in BAL injury measures after O
exposure. In conclusion, the method used for lavage and euthanasia affects measures of lung inflammation/injury and should be considered a variable in model assessments.
Interactions between air pollution and infectious agents are increasingly recognized and critical to identify, especially to protect vulnerable populations. Pregnancy represents a vulnerable period ...for influenza infection and air pollution exposure, yet interactions during pregnancy remain unclear. Maternal exposure to ultrafine particles (UFPs, Formula: see text 100 nm diameter), a class of particulate matter ubiquitous in urban environments, elicits unique pulmonary immune responses. We hypothesized that UFP exposure during pregnancy would lead to aberrant immune responses to influenza enhancing infection severity.
Building from our well-characterized C57Bl/6N mouse model employing daily gestational UFP exposure from gestational day (GD) 0.5-13.5, we carried out a pilot study wherein pregnant dams were subsequently infected with Influenza A/Puerto Rico/8/1934 (PR8) on GD14.5. Findings indicate that PR8 infection caused decreased weight gain in filtered air (FA) and UFP-exposed groups. Co-exposure to UFPs and viral infection led to pronounced elevation in PR8 viral titer and reduced pulmonary inflammation, signifying potential suppression of innate and adaptive immune defenses. Pulmonary expression of the pro-viral factor sphingosine kinase 1 (Sphk1) and pro-inflammatory cytokine interleukin-1β (IL-1 Formula: see text) was significantly increased in pregnant mice exposed to UFPs and infected with PR8; expression correlated with higher viral titer.
Results from our model provide initial insight into how maternal UFP exposure during pregnancy enhances respiratory viral infection risk. This model is an important first step in establishing future regulatory and clinical strategies for protecting pregnant women exposed to UFPs.
Introduction Environmental exposures and experimental manipulations can alter the ontogenetic composition of tissue-resident macrophages. However, the impact of these alterations on subsequent immune ...responses, particularly in allergic airway diseases, remains poorly understood. This study aims to elucidate the significance of modified macrophage ontogeny resulting from environmental exposures on allergic airway responses to house dust mite (HDM) allergen. Methods We utilized embryonic lineage labeling to delineate the ontogenetic profile of tissue-resident macrophages at baseline and following the resolution of repeated lipopolysaccharide (LPS)-induced lung injury. We investigated differences in house dust mite (HDM)-induced allergy to assess the influence of macrophage ontogeny on allergic airway responses. Additionally, we employed single-cell RNA sequencing (scRNAseq) and immunofluorescent staining to characterize the pulmonary macrophage composition, associated pathways, and tissue localization. Results Our findings demonstrate that the ontogeny of homeostatic alveolar and interstitial macrophages is altered after the resolution from repeated LPS-induced lung injury, leading to the replacement of embryonic-derived by bone marrow-derived macrophages. This shift in macrophage ontogeny is associated with reduced HDM-induced allergic airway responses. Through scRNAseq and immunofluorescent staining, we identified a distinct subset of resident-derived interstitial macrophages expressing genes associated with allergic airway diseases, localized adjacent to terminal bronchi, and diminished by prior LPS exposure. Discussion These results suggest a pivotal role for pulmonary macrophage ontogeny in modulating allergic airway responses. Moreover, our findings highlight the implications of prior environmental exposures in shaping future immune responses and influencing the development of allergies. By elucidating the mechanisms underlying these phenomena, this study provides valuable insights into potential therapeutic targets for allergic airway diseases and avenues for further research into immune modulation and allergic disease prevention.
Elevated ambient temperatures and extreme weather events have increased the incidence of wildfires world-wide resulting in increased wood smoke particle (WSP). Epidemiologic data suggests that WSP ...exposure associates with exacerbations of respiratory diseases, and with increased respiratory viral infections. To assess the impact of WSP exposure on host response to viral pneumonia, we performed WSP exposures in rodents followed by infection with mouse adapted influenza (HINI-PR8). C57BL/6 male mice aged 6–8 weeks were challenged with WSP or PBS by oropharyngeal aspiration in acute (single dose) or sub-acute exposures (day 1, 3, 5, 7 and 10). Additional groups underwent sub-acute exposure followed by infection by influenza or heat-inactivated (HI) virus. Following exposures/infection, bronchoalveolar lavage (BAL) was performed to assess for total cell counts/differentials, total protein, protein carbonyls and hyaluronan. Lung tissue was assessed for viral counts by real time PCR. When compared to PBS, acute WSP exposure associated with an increase in airspace macrophages. Alternatively, sub-acute exposure resulted in a dose dependent increase in airspace neutrophils. Sub-acute WSP exposure followed by influenza infection was associated with improved respiratory viral outcomes including reduced weight loss and increased blood oxygen saturation, and decreased protein carbonyls and viral titers. Flow cytometry demonstrated dynamic changes in pulmonary macrophage and T cell subsets based on challenge with WSP and influenza. This data suggests that sub-acute WSP exposure can improve host response to acute influenza infection.
•Sub-acute wood smoke particle (WSP) exposure in mice increases lung inflammation.•WSP exposure and subsequent influenza infection reduces influenza severity.•Improved severity associated with altered lung macrophages and viral gene expression.•This supports that WSP exposure reduces the severity of viral infection in mice.
Acute exposure models develop airway hyperresponsiveness (AHR), TH2-mediated airway inflammation, and mucus secretion,1,2 but airway remodeling with peribronchial collagen deposition requires chronic ...exposures.3-5 Presently there are no standard exposure methodologies, because each model varies with respect to the species, duration, and/or dose of HDM used and different exposure protocols affect phenotypic outcomes.4 In addition, phenotypic outcomes depend on the HDM extract source.6 Lack of reproducible physiological responses to allergen extracts has long been known and is well documented in mice and humans after cutaneous exposure,7,8 but has been less well detailed in models of allergen inhalation. Furthermore, HDM dose normalization in these studies can be based on protein content, antigen content, or dry extract weight. Because HDM extracts are prepared from live mites, and the allergen and endotoxin content can differ between preparations, we hypothesized that the response to extracts may differ among lots even when prepared from the same commercial supplier and used in the same exposure protocol. Interestingly, after chronic exposure (oropharyngeal aspiration 100 μg 3×/wk for 5 weeks), HDM0 challenge resulted in AHR to methacholine, whereas HDM1 did not (Fig 1, B). Because of the striking differences in AHR, we evaluated respiratory mechanics after chronic exposure to several HDM lots containing different concentrations of total protein, antigen, and endotoxin (see Table E2 in this article's Online Repository at www.jacionline.org). ...although allergen extracts are becoming a powerful tool for studying allergy, asthma, and airway disease in animal models, our data demonstrate that these extracts are complex mixtures that can result in variable phenotypic responses, and studies should proceed with caution. Because of the variability in components within the extracts, it is important to describe both the lot characteristics and the methods used to normalize dosing so that concentrations of specific components can be calculated and compared between studies.