CXCL1 regulates neutrophil homeostasis in pneumonia-derived sepsis caused by Streptococcus pneumoniae serotype 3

Abstract Neutrophil migration to the site of bacterial infection is a critical step in host defense. Exclusively produced in the bone marrow, neutrophil release into the blood is tightly controlled. Although the chemokine CXCL1 induces neutrophil influx during bacterial infections, its role in regulating neutrophil recruitment, granulopoiesis, and neutrophil mobilization in response to lung infection-induced sepsis is unclear. Here, we used a murine model of intrapulmonary Streptococcus pneumoniae infection to investigate the role of CXCL1 in host defense, granulopoiesis, and neutrophil mobilization. Our results demonstrate that CXCL1 augments neutrophil influx to control bacterial growth in the lungs, as well as bacterial dissemination, resulting in improved host survival. This was shown in Cxcl1−/− mice, which exhibited defective amplification of early neutrophil precursors in granulocytic compartments, and CD62L- and CD49d-dependent neutrophil release from the marrow. Administration of recombinant CXCL2 and CXCL5 after infection rescues the impairments in neutrophil-dependent host defense in Cxcl1−/− mice. Taken together, these findings identify CXCL1 as a central player in host defense, granulopoiesis, and mobilization of neutrophils during Gram-positive bacterial pneumonia-induced sepsis.

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Increased lethality and defective pulmonary clearance of Streptococcus pneumoniae in microsomal prostaglandin E synthase-1-knockout mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00220.2015 ◽

2016 ◽

Vol 310 (11) ◽

pp. L1111-L1120 ◽

Cited By ~ 8

Author(s):

Jennifer M. Dolan ◽

Jason B. Weinberg ◽

Edmund O'Brien ◽

Anya Abashian ◽

Megan C. Procario ◽

...

Keyword(s):

Nitric Oxide ◽

Streptococcus Pneumoniae ◽

Host Defense ◽

Bacterial Pneumonia ◽

Bacterial Infections ◽

Pneumococcal Pneumonia ◽

Prostaglandin E ◽

Prostaglandin E Synthase

The production of prostaglandin E2 (PGE2) increases dramatically during pneumococcal pneumonia, and this lipid mediator impairs alveolar macrophage (AM)-mediated innate immune responses. Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme involved in the synthesis of PGE2, and its expression is enhanced during bacterial infections. Genetic deletion of mPGES-1 in mice results in diminished PGE2 production and elevated levels of other prostaglandins after infection. Since PGE2 plays an important immunoregulatory role during bacterial pneumonia we assessed the impact of mPGES-1 deletion in the host defense against pneumococcal pneumonia in vivo and in AMs in vitro. Wild-type (WT) and mPGES-1 knockout (KO) mice were challenged with Streptococcus pneumoniae via the intratracheal route. Compared with WT animals, we observed reduced survival and increased lung and spleen bacterial burdens in mPGES-1 KO mice 24 and 48 h after S. pneumoniae infection. While we found modest differences between WT and mPGES-1 KO mice in pulmonary cytokines, AMs from mPGES-1 KO mice exhibited defective killing of ingested bacteria in vitro that was associated with diminished inducible nitric oxide synthase expression and reduced nitric oxide (NO) synthesis. Treatment of AMs from mPGES-1 KO mice with an NO donor restored bacterial killing in vitro. These results suggest that mPGES-1 plays a critical role in bacterial pneumonia and that genetic ablation of this enzyme results in diminished pulmonary host defense in vivo and in vitro. These results suggest that specific inhibition of PGE2 synthesis by targeting mPGES-1 may weaken host defense against bacterial infections.

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Role of Autophagy and Apoptosis in the Postinfluenza Bacterial Pneumonia

BioMed Research International ◽

10.1155/2016/3801026 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Zhen Qin ◽

Yuan Yang ◽

Hongren Wang ◽

Jun Luo ◽

Xiaojun Huang ◽

...

Keyword(s):

Bacterial Infection ◽

Influenza A Virus ◽

Bacterial Pneumonia ◽

Influenza A ◽

Bacterial Infections ◽

Research Progress ◽

The Past ◽

Recent Research Progress ◽

Increased Susceptibility

The risk of influenza A virus (IAV) is more likely caused by secondary bacterial infections. During the past decades, a great amount of studies have been conducted on increased morbidity from secondary bacterial infections following influenza and provide an increasing number of explanations for the mechanisms underlying the infections. In this paper, we first review the recent research progress that IAV infection increased susceptibility to bacterial infection. We then propose an assumption that autophagy and apoptosis manipulation are beneficial to antagonize post-IAV bacterial infection and discuss the clinical significance.

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Initial recruitment of neutrophils to alveolar structures in acute lung injury

Journal of Applied Physiology ◽

10.1152/jappl.1991.70.4.1575 ◽

1991 ◽

Vol 70 (4) ◽

pp. 1575-1585 ◽

Cited By ~ 14

Author(s):

G. C. Kindt ◽

J. E. Gadek ◽

J. E. Weiland

Keyword(s):

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Bronchoalveolar Lavage ◽

Bacterial Pneumonia ◽

Bronchoalveolar Lavage Fluid ◽

Distress Syndrome ◽

Neutrophil Migration ◽

Lavage Fluid ◽

Neutrophil Influx ◽

Lung Lymph

The adult respiratory distress syndrome and bacterial pneumonia are both characterized by an influx of neutrophils into the lung. The neutrophil has been implicated as having a “pathological” role in adult respiratory distress syndrome, in contrast to its role in bacterial pneumonia. We hypothesized that processes resulting in neutrophil recruitment to the lung are distinct, depending on whether the inflammatory stimulus arises in the intravascular or the alveolar compartment of the lung. Anesthetized sheep with lung lymph fistulas were utilized to access the three compartments of the lung relevant to studies of transpulmonary neutrophil migration. Serum, lung lymph, and bronchoalveolar lavage fluid were studied for neutrophil influx and chemotactic activity before and after administration of endotoxin by either an intravascular or inhaled alveolar route. Both groups developed significant neutrophil influx into the lymph and bronchoalveolar lavage fluid by 3 h postendotoxin. Those animals receiving intravascular endotoxin developed chemotactic gradients opposing neutrophil migration into the lung in contrast to animals receiving alveolar endotoxin, suggesting that neutrophil influx into the lung occurs by random migration.

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Role of interferon-γ in Vα14+ natural killer T cell-mediated host defense against Streptococcus pneumoniae infection in murine lungs

Microbes and Infection ◽

10.1016/j.micinf.2006.12.003 ◽

2007 ◽

Vol 9 (3) ◽

pp. 364-374 ◽

Cited By ~ 70

Author(s):

Masashi Nakamatsu ◽

Natsuo Yamamoto ◽

Masumitsu Hatta ◽

Chikara Nakasone ◽

Takeshi Kinjo ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

T Cell ◽

Natural Killer ◽

Host Defense ◽

Interferon Γ ◽

Natural Killer T Cell ◽

Killer T Cell ◽

Natural Killer T

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Role of Specialized Pro-Resolving Mediators in Modifying Host Defense and Decreasing Bacterial Virulence

Molecules ◽

10.3390/molecules26226970 ◽

2021 ◽

Vol 26 (22) ◽

pp. 6970

Author(s):

Julianne M. Thornton ◽

Kingsley Yin

Keyword(s):

Host Defense ◽

Host Response ◽

Tissue Repair ◽

Defense Mechanisms ◽

Neutrophil Migration ◽

Bacterial Virulence ◽

Innate Immune ◽

Bioactive Fatty Acids ◽

Insight Into

Bacterial infection activates the innate immune system as part of the host’s defense against invading pathogens. Host response to bacterial pathogens includes leukocyte activation, inflammatory mediator release, phagocytosis, and killing of bacteria. An appropriate host response requires resolution. The resolution phase involves attenuation of neutrophil migration, neutrophil apoptosis, macrophage recruitment, increased phagocytosis, efferocytosis of apoptotic neutrophils, and tissue repair. Specialized Pro-resolving Mediators (SPMs) are bioactive fatty acids that were shown to be highly effective in promoting resolution of infectious inflammation and survival in several models of infection. In this review, we provide insight into the role of SPMs in active host defense mechanisms for bacterial clearance including a new mechanism of action in which an SPM acts directly to reduce bacterial virulence.

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B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

Infection and Immunity ◽

10.1128/iai.02639-14 ◽

2014 ◽

Vol 83 (2) ◽

pp. 743-758 ◽

Cited By ~ 9

Author(s):

Teri R. Hoyt ◽

Erin Dobrinen ◽

Irina Kochetkova ◽

Nicole Meissner

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

Lung Infection ◽

Type I ◽

Type I Ifn ◽

Content Type ◽

On Demand ◽

Type I Ifns

HIV infection results in a complex immunodeficiency due to loss of CD4+T cells, impaired type I interferon (IFN) responses, and B cell dysfunctions causing susceptibility to opportunistic infections such asPneumocystis murinapneumonia and unexplained comorbidities, including bone marrow dysfunctions. Type I IFNs and B cells critically contribute to immunity toPneumocystislung infection. We recently also identified B cells as supporters of on-demand hematopoiesis followingPneumocystisinfection that would otherwise be hampered due to systemic immune effects initiated in the context of a defective type I IFN system. While studying the role of type I IFNs in immunity toPneumocystisinfection, we discovered that mice lacking both lymphocytes and type I IFN receptor (IFrag−/−) developed progressive bone marrow failure following infection, while lymphocyte-competent type I IFN receptor-deficient mice (IFNAR−/−) showed transient bone marrow depression and extramedullary hematopoiesis. Lymphocyte reconstitution of lymphocyte-deficient IFrag−/−mice pointed to B cells as a key player in bone marrow protection. Here we define how B cells protect on-demand hematopoiesis followingPneumocystis lung infection in our model. We demonstrate that adoptive transfer of B cells into IFrag−/−mice protects early hematopoietic progenitor activity during systemic responses toPneumocystisinfection, thus promoting replenishment of depleted bone marrow cells. This activity is independent of CD4+T cell help and B cell receptor specificity and does not require B cell migration to bone marrow. Furthermore, we show that B cells protect on-demand hematopoiesis in part by induction of interleukin-10 (IL-10)- and IL-27-mediated mechanisms. Thus, our data demonstrate an important immune modulatory role of B cells duringPneumocystislung infection that complement the modulatory role of type I IFNs to prevent systemic complications.

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mSphere of Influence: Adenosine in Host Defense against Bacterial Pneumonia—Friend or Foe?

mSphere ◽

10.1128/msphere.00326-19 ◽

2019 ◽

Vol 4 (4) ◽

Cited By ~ 1

Author(s):

Elsa N. Bou Ghanem

Keyword(s):

Host Defense ◽

Bacterial Pneumonia ◽

Pneumococcal Pneumonia ◽

Respir Crit ◽

Innate Immune ◽

Immune Senescence ◽

Host Defenses ◽

Extracellular Adenosine ◽

Gram Negative

ABSTRACT Elsa N. Bou Ghanem works in the field of innate immune senescence, inflammation, and host defense. In this mSphere of Influence article, she reflects on how “Adenosine A2B receptor deficiency promotes host defenses against Gram-negative bacterial pneumonia” by Barletta et al. (K. E. Barletta, R. E. Cagnina, M. D. Burdick, J. Linden, and B. Mehrad, Am J Respir Crit Care Med 186:1044–1050, 2012, https://doi.org/10.1164/rccm.201204-0622OC) impacted her own work examining the role of the extracellular adenosine pathway in neutrophil responses and host defense against pneumococcal pneumonia.

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Eﬀect of CARD9 Deficiency on Neutrophil-Mediated Host Defense against Pulmonary Infection with Streptococcus pneumoniae

Infection and Immunity ◽

10.1128/iai.00305-20 ◽

2020 ◽

Vol 89 (1) ◽

pp. e00305-20

Author(s):

Shigenari Ishizuka ◽

Rin Yokoyama ◽

Ko Sato ◽

Ryuhei Shiroma ◽

Ayako Nakahira ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Host Defense ◽

Alveolar Macrophages ◽

Neutrophil Migration ◽

Pneumococcal Infection ◽

Neutrophil Accumulation ◽

Necrosis Factor Alpha ◽

Chemokine Production ◽

Lectin Receptors ◽

Tnf Α

ABSTRACTStreptococcus pneumoniae is a major causative bacterium of community-acquired pneumonia. Dendritic cell-associated C-type lectin-2 (dectin-2), one of the C-type lectin receptors (CLRs), was previously reported to play a pivotal role in host defense against pneumococcal infection through regulating phagocytosis by neutrophils while not being involved in neutrophil accumulation. In the present study, to elucidate the possible contribution of other CLRs to neutrophil accumulation, we examined the role of caspase recruitment domain-containing protein 9 (CARD9), a common adaptor molecule for signal transduction triggered by CLRs, in neutrophilic inflammatory response against pneumococcal infection. Wild-type (WT), CARD9 knockout (KO), and dectin-2 KO mice were infected intratracheally with pneumococcus, and the infected lungs were histopathologically analyzed to assess neutrophil accumulation at 24 h postinfection. Bronchoalveolar lavage fluids (BALFs) were collected at the same time point to count the neutrophils and assess the production of inflammatory cytokines and chemokines. Neutrophil accumulation was significantly decreased in CARD9 KO mice, but not in dectin-2 KO mice. Tumor necrosis factor alpha (TNF-α), keratinocyte-derived chemokine (KC), and macrophage inflammatory protein-2 (MIP-2) production in BALFs were also attenuated in CARD9 KO mice, but not in dectin-2 KO mice. Production of TNF-α and KC by alveolar macrophages stimulated with pneumococcal culture supernatants was significantly attenuated in CARD9 KO mice, but not in dectin-2 KO mice, compared to that in each group’s respective control mice. In addition, pneumococcus-infected CARD9 KO mice showed larger bacterial burdens in the lungs than did WT mice. These data indicate that CARD9 is required for neutrophil migration after pneumococcal infection, as well as inflammatory cytokine and chemokine production by alveolar macrophages, and suggest that a CLR distinct from dectin-2 may be involved in this response.

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