Mast Cells Protect against Pseudomonas aeruginosa–Induced Lung Injury

Junkins, Robert D.; Carrigan, Svetlana O.; Wu, Zhengli; Stadnyk, Andrew W.; Cowley, Elizabeth A.; Issekutz, Thomas B.; Berman, Jason N.; Lin, Tong‐Jun

doi:10.1016/j.ajpath.2014.05.009

Cited by 15 publications

(13 citation statements)

References 86 publications

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“…aeruginosa lung infection via unique mechanisms. Previously, we demonstrated essential roles of macrophages[ 29 ], mast cells[ 43 ] and dendritic cells[ 44 ] in an acute P . aeruginosa infection model.…”

Section: Discussionmentioning

confidence: 99%

CXCL4 contributes to host defense against acute Pseudomonas aeruginosa lung infection

Yue

Pang

et al. 2018

PLoS ONE

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Platelets have been implicated in pulmonary inflammation following exposure to bacterial stimuli. The mechanisms involved in the platelet-mediated host response to respiratory bacterial infection remain incompletely understood. In this study, we demonstrate that platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) plays critical roles in a mouse model of acute bacterial pneumonia using Pseudomonas aeruginosa. Platelets are activated during P. aeruginosa infection, and mice depleted of platelets display markedly increased mortality and impaired bacterial clearance. CXCL4 deficiency impairs bacterial clearance and lung epithelial permeability, which correlate with decreased neutrophil recruitment to BALF. Interestingly, CXCL4 deficiency selectively regulates chemokine production, suggesting that CXCL4 has an impact on other chemokine expression. In addition, CXCL4 deficiency reduces platelet-neutrophil interactions in blood following P. aeruginosa infection. Further studies revealed that platelet-derived CXCL4 contributes to the P. aeruginosa-killing of neutrophils. Altogether, these findings demonstrate that CXCL4 is a vital chemokine that plays critical roles in bacterial clearance during P. aeruginosa infection through recruiting neutrophils to the lungs and intracellular bacterial killing.

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Section: Discussionmentioning

confidence: 99%

CXCL4 contributes to host defense against acute Pseudomonas aeruginosa lung infection

Yue

Pang

et al. 2018

PLoS ONE

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“…The models of the P. aeruginosa induced-pneumonia used in the present study are highly relevant to clinical situations of ARDS [ 30 , 31 ]. We observed that HNP + mice had much lower bacterial count than FVB mice in pneumonia conditions.…”

Section: Discussionmentioning

confidence: 99%

Dual effects of human neutrophil peptides in a mouse model of pneumonia and ventilator-induced lung injury

et al. 2018

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BackgroundPneumonia is a major cause of high morbidity and mortality in critically illness, and frequently requires support with mechanical ventilation. The latter can lead to ventilator-induced lung injury characterized by neutrophil infiltration. The cationic human neutrophil peptides (HNP) stored in neutrophils can kill microorganisms, but excessive amount of HNP released during phagocytosis may contribute to inflammatory responses and worsen lung injury. Based on our previous work, we hypothesized that blocking the cell surface purinergic receptor P2Y6 will attenuate the HNP-induced inflammatory responses while maintaining their antimicrobial activity in pneumonia followed by mechanical ventilation.MethodsPlasma HNP levels were measured in patients with pneumonia who received mechanical ventilation and in healthy volunteers. FVB littermate control and HNP transgenic (HNP+) mice were randomized to receive P. aeruginosa intranasally. The P2Y6 antagonist (MRS2578) or vehicle control was given after P. aeruginosa instillation. Additional mice underwent mechanical ventilation at either low pressure (LP) or high pressure (HP) ventilation 48 h after pneumonia, and were observed for 24 h.ResultsPlasma HNP concentration increased in patients with pneumonia as compared to healthy subjects. The bacterial counts in the bronchoalveolar lavage fluid (BALF) were lower in HNP+ mice than in FVB mice 72 h after P. aeruginosa instillation. However, upon receiving HP ventilation, HNP+ mice had higher levels of cytokines and chemokines in BALF than FVB mice. These inflammatory responses were attenuated by the treatment with MRS2578 that did not affect the microbial effects of HNP.ConclusionsHNP exerted dual effects by exhibiting antimicrobial activity in pneumonia alone condition while enhancing inflammatory responses in pneumonia followed by HP mechanical ventilation. Blocking P2Y6 can attenuate the inflammation without affecting the antibacterial property of HNP. The P2Y6 receptor may be a novel therapeutic target in attenuation of the leukocyte-mediated excessive host responses in inflammatory lung diseases.

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“…The protective effect was linked to mast cell-mediated promotion of neutrophil recruitment to sites of infection through their release of pro-inflammatory mediators ( 17 , 18 ). Subsequently, numerous reports were published corroborating this initial observation in various experimental infectious disease models including, for instance, Citrobacter rodentium -induced colitis ( 19 ), experimental cystitis due to Escherichia coli infection ( 20 ), Staphylococcus aureus peptidoglycan-triggered diarrhea ( 21 ), Salmonella minnesota lipopolysaccharide-induced peritonitis ( 22 ), and Pseudomonas aeruginosa pneumonia ( 23 ), or encephalomyocarditis viral myocarditis ( 24 ). However, recent studies using two or more mast cell-deficient Kit mutant mouse strains and/or mutant mouse strains with unperturbed c-Kit function revealed a more complicated picture: depending on the nature of the mutation resulting in a mast cell deficiency as well as the type and severity of infection, mast cells can have no effect, aggravate, or attenuate inflammation and infectious disease severity ( 25 – 28 ).…”

Section: Introductionmentioning

confidence: 87%

Mast Cells Are Activated by Streptococcus pneumoniae In Vitro but Dispensable for the Host Defense Against Pneumococcal Central Nervous System Infection In Vivo

et al. 2018

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Mast cells reside on and near the cerebral vasculature, the predominant site of pneumococcal entry into the central nervous system (CNS). Although mast cells have been reported to be crucial in protecting from systemic bacterial infections, their role in bacterial infections of the CNS remained elusive. Here, we assessed the role of mast cells in pneumococcal infection in vitro and in vivo. In introductory experiments using mouse bone marrow-derived mast cells (BMMC), we found that (i) BMMC degranulate and release selected cytokines upon exposure to Streptococcus pneumoniae, (ii) the response of BMMC varies between different pneumococcal serotypes and (iii) is dependent on pneumolysin. Intriguingly though, apart from a slight enhancement of cerebrospinal fluid (CSF) pleocytosis, neither two different mast cell-deficient Kit mutant mouse strains (WBB6F1-KitW/Wv and C57BL/6 KitW-sh/W-sh mice) nor pharmacologic mast cell stabilization with cromoglycate had any significant impact on the disease phenotype of experimental pneumococcal meningitis. The incomplete reversal of the enhanced CSF pleocytosis by local mast cell engraftment suggests that this phenomenon is caused by other c-Kit mutation-related mechanisms than mast cell deficiency. In conclusion, our study suggests that mast cells can be activated by S. pneumoniae in vitro. However, mast cells do not play a significant role as sentinels of pneumococcal CSF invasion and initiators of innate immunity in vivo.

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Mast Cells Protect against Pseudomonas aeruginosa–Induced Lung Injury

Cited by 15 publications

References 86 publications

CXCL4 contributes to host defense against acute Pseudomonas aeruginosa lung infection

CXCL4 contributes to host defense against acute Pseudomonas aeruginosa lung infection

Dual effects of human neutrophil peptides in a mouse model of pneumonia and ventilator-induced lung injury

Mast Cells Are Activated by Streptococcus pneumoniae In Vitro but Dispensable for the Host Defense Against Pneumococcal Central Nervous System Infection In Vivo

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