Alveolar Macrophage Apoptosis–associated Bacterial Killing Helps Prevent Murine Pneumonia

Preston, Julie A.; Bewley, Martin A.; Marriott, Helen M.; Houghton, A. McGarry; Mohasin, Mohammed; Jubrail, Jamil; Morris, Lucy; Stephenson, Yvonne; Cross, Simon S.; Greaves, David R.; Craig, Ruth W.; Rooijen, Nico van; Bingle, Colin D.; Read, Robert C.; Mitchell, Timothy J.; Whyte, Moira K. B.; Shapiro, Steven D.; Dockrell, David H.

doi:10.1164/rccm.201804-0646oc

Cited by 46 publications

(52 citation statements)

References 53 publications

(66 reference statements)

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“…This hypothesis‐testing study was based on evidence suggesting that N‐BPs may have similar effects on both alveolar macrophages and osteoclasts, cells that share the same lineage, and thus may influence the pathogenesis of pneumonia characterized by lung parenchyma inflammation. Alveolar macrophages play an important antibacterial role in defending against pneumonia by early phagocytosis of pathogens and subsequent induction of apoptosis to minimize inflammation . A clinical study showed that N‐BPs reduced macrophage lineage cells through the reduction of mcl‐1 expressions in both macrophages and osteoclasts, which might subsequently reduce inflammation .…”

Section: Discussionmentioning

confidence: 99%

Nitrogen-Containing Bisphosphonates Are Associated With Reduced Risk of Pneumonia in Patients With Hip Fracture

Sing

Kiel

Hubbard

et al. 2020

Journal of Bone and Mineral Research

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The objective of this work was to study the risk of pneumonia and pneumonia mortality among patients receiving nitrogen‐containing bisphosphonates (N‐BPs), non‐N‐BP anti‐osteoporosis medications, and no anti‐osteoporosis medications after hip fracture. We studied a historical cohort using a population‐wide database. Patients with first hip fracture during 2005–2015 were identified and matched by time‐dependent propensity score. The cohort was followed until December 31, 2016, to capture any pneumonia and pneumonia mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox‐proportional hazards regression. Absolute risk difference (ARD) and number needed to treat (NNT) were calculated. We identified 54,047 patients with hip fracture. Of these, 4041 patients who received N‐BPs and 11,802 without anti‐osteoporosis medication were propensity score–matched. N‐BPs were associated with a significantly lower risk of pneumonia compared with no treatment (6.9 versus 9.0 per 100 person‐years; HR 0.76; 95% CI, 0.70 to 0.83), resulting in an ARD of 0.02 and NNT of 46. A similar association was observed with pneumonia mortality (HR 0.65; 95% CI, 0.56 to 0.75). When N‐BPs were compared with non‐N‐BP anti‐osteoporosis medications, the association remained significant. N‐BPs were associated with lower risks of pneumonia and pneumonia mortality. Randomized controlled trials are now required to determine whether N‐BPs, non–vaccine‐based medications, can reduce pneumonia incidence in high risk groups. © 2020 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Nitrogen-Containing Bisphosphonates Are Associated With Reduced Risk of Pneumonia in Patients With Hip Fracture

Sing

Kiel

Hubbard

et al. 2020

Journal of Bone and Mineral Research

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“…We postulated that differential expression of key pattern recognition receptors such as CD209b might endow female macrophages with an enhanced ability to deal with bacterial infection. To test this idea, we examined the acute peritonitis caused by the gram-positive bacterium Streptococcus pneumoniae (Figure 7a), a localised model of infection in which resident macrophages, and in particular CD209b, are indispensable for protective immunity 49, 50 whereas recruitment of neutrophils is not required 49 and hence avoids any confounding effects of systemic sex-dependent effects on innate immune responses that have been reported previously 51 . As CD209b is expressed exclusively by CD102 + macrophages in the peritoneal cavity ( Supplementary Figure 6 ), this model allowed us to directly assess the importance of differential CD209b expression by CD102 + macrophages in bacterial elimination.…”

Section: Resultsmentioning

confidence: 99%

Origin and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages

Bain

Gibson

Steers

et al. 2019

Preprint

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Macrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the aetiology of pathologies including peritonitis, endometriosis and metastatic cancer thus understanding the factors that govern their behaviour is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and age on murine peritoneal macrophage differentiation, turnover and function. We demonstrate that the sexually dimorphic replenishment of peritoneal macrophages from the bone marrow, which is high in males and very low in females, is driven by changes in the local microenvironment that arise upon sexual maturation. Population and single cell RNAseq revealed striking dimorphisms in gene expression between male and female peritoneal macrophages that was in part explained by differences in composition of these populations. By estimating the time of residency of different subsets within the cavity and assessing development of dimorphisms with age and in monocytopenic Ccr2−/− mice, we demonstrate that key sex-dependent features of peritoneal macrophages are a function of the differential rate of replenishment from the bone marrow while others are reliant on local microenvironment signals. Importantly, we demonstrate that the dimorphic turnover of peritoneal macrophages contributes to differences in the ability to protect against pneumococcal peritonitis between the sexes. These data highlight the importance of considering both sex and age in susceptibility to inflammatory and infectious disease.

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“…Across pneumococcal strains, those that more rapidly induce necroptosis tend to be more virulent in the lung (27), suggesting this mode of cell death to be a maladaptive pathway during pneumococcal pneumonia. In contrast, macrophage cell death by apoptosis appears to be a healthy response to pneumococcal infcetion, since specifically preventing macrophage apoptosis results in more severe lung infections (46). Pneumococcusinduced macrophage death is a complicated but important contributor to pneumonia outcomes.…”

Section: Discussionmentioning

confidence: 99%

Unique Roles for Streptococcus pneumoniae Phosphodiesterase 2 in Cyclic di-AMP Catabolism and Macrophage Responses

et al. 2020

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Cyclic di-AMP (c-di-AMP) is an important signaling molecule for pneumococci, and as a uniquely prokaryotic product it can be recognized by mammalian cells as a danger signal that triggers innate immunity. Roles of c-di-AMP in directing host responses during pneumococcal infection are only beginning to be defined. We hypothesized that pneumococci with defective c-di-AMP catabolism due to phosphodiesterase deletions could illuminate roles of c-di-AMP in mediating host responses to pneumococcal infection. Pneumococci deficient in phosphodiesterase 2 (Pde2) stimulated a rapid induction of interferon β (IFNβ) expression that was exaggerated in comparison to that induced by wild type (WT) bacteria or bacteria deficient in phosphodiesterase 1. This IFNβ burst was elicited in mouse and human macrophage-like cell lines as well as in primary alveolar macrophages collected from mice with pneumococcal pneumonia. Macrophage hyperactivation by Pde2-deficient pneumococci led to rapid cell death. STING and cGAS were essential for the excessive IFNβ induction, which also required phagocytosis of bacteria and triggered the phosphorylation of IRF3 and IRF7 transcription factors. The select effects of Pde2 deletion were products of a unique role of this enzyme in c-di-AMP catabolism when pneumococci were grown on solid substrate conditions designed to enhance virulence. Because pneumococci with elevated c-di-AMP drive aberrant innate immune responses from macrophages involving hyperactivation of STING, excessive IFNβ expression, and rapid cytotoxicity, we surmise that c-di-AMP is pivotal for directing innate immunity and host-pathogen interactions during pneumococcal pneumonia.

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Alveolar Macrophage Apoptosis–associated Bacterial Killing Helps Prevent Murine Pneumonia

Abstract: This is a repository copy of Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia.

Cited by 46 publications

References 53 publications

Nitrogen-Containing Bisphosphonates Are Associated With Reduced Risk of Pneumonia in Patients With Hip Fracture

Nitrogen-Containing Bisphosphonates Are Associated With Reduced Risk of Pneumonia in Patients With Hip Fracture

Origin and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages

Unique Roles for Streptococcus pneumoniae Phosphodiesterase 2 in Cyclic di-AMP Catabolism and Macrophage Responses

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