scholarly journals Toll-Like Receptor 2 Regulates CXC Chemokine Production and Neutrophil Recruitment to the Cornea in Onchocerca volvulus/ Wolbachia-Induced Keratitis

2007 ◽  
Vol 75 (12) ◽  
pp. 5908-5915 ◽  
Author(s):  
Illona Gillette-Ferguson ◽  
Katrin Daehnel ◽  
Amy G. Hise ◽  
Yan Sun ◽  
Eric Carlson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Essential Role ◽  
Corneal Stroma ◽  
Neutrophil Activation ◽  
Neutrophil Recruitment ◽  
Onchocerca Volvulus ◽  
Chemokine Production ◽  
Corneal Haze ◽  
Cxc Chemokine ◽  
Bone Marrow Derived Cells

ABSTRACT The filarial nematode Onchocerca volvulus is the causative organism of river blindness. Our previous studies demonstrated an essential role for endosymbiotic Wolbachia bacteria in corneal disease, which is characterized by neutrophil infiltration into the corneal stroma and the development of corneal haze. To determine the role of Toll-like receptors (TLRs) in neutrophil recruitment and activation, we injected a soluble extract of O. volvulus containing Wolbachia bacteria into the corneal stromata of C57BL/6, TLR2−/−, TLR4−/−, TLR2/4−/−, and TLR9−/− mice. We found an essential role for TLR2, but not TLR4 or TLR9, in neutrophil recruitment to the cornea and development of corneal haze. Furthermore, chimeric mouse bone marrow studies showed that resident bone marrow-derived cells in the cornea can initiate this response. TLR2 expression was also essential for CXC chemokine production by resident cells in the cornea, including corneal fibroblasts, and for neutrophil activation. Taken together, these findings indicate that Wolbachia activates TLR2 on resident bone marrow-derived cells in the corneal stroma to produce CXC chemokines, leading to neutrophil recruitment to the corneal stroma, and that TLR2 mediates O. volvulus/Wolbachia-induced neutrophil activation and development of corneal haze.

scholarly journals Gamma Interferon and Interleukin-1 Receptor 1 Regulate Neutrophil Recruitment to the Corneal Stroma in a Murine Model of Onchocerca volvulus Keratitis

2009 ◽  
Vol 77 (4) ◽  
pp. 1606-1612 ◽  
Author(s):  
Katrin Gentil ◽  
Eric Pearlman
Keyword(s):  
Corneal Stroma ◽  
Gamma Interferon ◽  
Neutrophil Recruitment ◽  
Onchocerca Volvulus ◽  
Eosinophil Infiltration ◽  
Chemokine Production ◽  
Corneal Fibroblasts ◽  
Cxc Chemokine ◽  
Ifn Γ

ABSTRACT Toll-like receptor 2 (TLR2) is an essential mediator of corneal inflammation induced by the filarial nematode Onchocerca volvulus, which harbors endosymbiotic Wolbachia bacteria. TLR2 is also required for dendritic cell activation, gamma interferon (IFN-γ) production, and neutrophil recruitment to the cornea. To examine the role of IFN-γ in O. volvulus keratitis, C57BL/6 and IFN-γ−/− mice were immunized subcutaneously, and a soluble antigen extract from O. volvulus adult worms (OvAg) was injected into the corneal stroma of each animal. We found that, in the absence of IFN-γ, neutrophil recruitment to the cornea was significantly impaired, whereas there was no effect on eosinophil infiltration. Since the cornea contains resident macrophages and fibroblasts and our previous studies showed that CXC chemokines mediate neutrophil recruitment, we examined the role of recombinant IFN-γ (rIFN-γ) on each cell type. We found no effect of rIFN-γ on CXC chemokine production by macrophages or corneal fibroblasts, either alone or with filarial extracts; in contrast, rIFN-γ was found to enhance OvAg-induced tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-1α, and IL-1β in macrophages. Furthermore, we found that rTNF-α, rIL-1α, or rIL-1β induced CXC chemokine production by corneal fibroblasts but not by macrophages. To determine the relative contributions of endogenous cytokines, we injected OvAg into the corneal stroma of C57BL/6, IL-1 receptor 1−/− (IL-1R1−/−), and TNF-αR1/2−/− mice and examined neutrophil recruitment. We found that neutrophil infiltration was impaired in IL-1R1−/− mice but not in TNF-αR1/2−/− mice. IFN-γ therefore appears to regulate neutrophil recruitment to the corneal stroma by enhancing TLR2 expression and OvAg-induced IL-1α and IL-1β production by macrophages in the cornea, which then induce IL-1R1-dependent production of CXC chemokine by resident corneal fibroblasts.

Geranylgeranyl transferase regulates CXC chemokine formation in alveolar macrophages and neutrophil recruitment in septic lung injury

2013 ◽  
Vol 304 (4) ◽  
pp. L221-L229 ◽  
Author(s):  
Zirak Hasan ◽  
Milladur Rahman ◽  
Karzan Palani ◽  
Ingvar Syk ◽  
Bengt Jeppsson ◽  
...  
Keyword(s):  
Lung Injury ◽  
Alveolar Macrophages ◽  
Neutrophil Infiltration ◽  
Abdominal Sepsis ◽  
Neutrophil Recruitment ◽  
Chemokine Production ◽  
Tnf Α ◽  
Cxc Chemokine ◽  
Geranylgeranyl Transferase

Overwhelming accumulation of neutrophils is a significant component in septic lung damage, although the signaling mechanisms behind neutrophil infiltration in the lung remain elusive. In the present study, we hypothesized that geranylgeranylation might regulate the inflammatory response in abdominal sepsis. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets. Gene expression of CXC chemokines, tumor necrosis factor-α (TNF-α), and CCL2 chemokine was determined by quantitative RT-PCR in isolated alveolar macrophages. Administration of GGTI-2133 markedly decreased CLP-induced infiltration of neutrophils, edema, and tissue injury in the lung. CLP triggered clear-cut upregulation of Mac-1 on neutrophils. Inhibition of geranylgeranyl transferase reduced CLP-evoked upregulation of Mac-1 on neutrophils in vivo but had no effect on chemokine-induced expression of Mac-1 on isolated neutrophils in vitro. Notably, GGTI-2133 abolished CLP-induced formation of CXC chemokines, TNF-α, and CCL2 in alveolar macrophages in the lung. Geranylgeranyl transferase inhibition had no effect on sepsis-induced platelet shedding of CD40L. In addition, inhibition of geranylgeranyl transferase markedly decreased CXC chemokine-triggered neutrophil chemotaxis in vitro. Taken together, our findings suggest that geranylgeranyl transferase is an important regulator of CXC chemokine production and neutrophil recruitment in the lung. We conclude that inhibition of geranylgeranyl transferase might be a potent way to attenuate acute lung injury in abdominal sepsis.

scholarly journals Requirement of Interleukin 17 Receptor Signaling for Lung Cxc Chemokine and Granulocyte Colony-Stimulating Factor Expression, Neutrophil Recruitment, and Host Defense

2001 ◽  
Vol 194 (4) ◽  
pp. 519-528 ◽  
Author(s):  
Peng Ye ◽  
Fred H. Rodriguez ◽  
Suzanne Kanaly ◽  
Kim L. Stocking ◽  
Jill Schurr ◽  
...  
Keyword(s):  
Bacterial Pneumonia ◽  
Neutrophil Recruitment ◽  
Interleukin 17 ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Chemokine Production ◽  
Inflammatory Protein ◽  
Cxc Chemokine ◽  
Cd4 Lymphocyte ◽  
Stimulating Factor

Bacterial pneumonia is an increasing complication of HIV infection and inversely correlates with the CD4+ lymphocyte count. Interleukin (IL)-17 is a cytokine produced principally by CD4+ T cells, which induces granulopoiesis via granulocyte colony-stimulating factor (G-CSF) production and induces CXC chemokines. We hypothesized that IL-17 receptor (IL-17R) signaling is critical for G-CSF and CXC chemokine production and lung host defenses. To test this, we used a model of Klebsiella pneumoniae lung infection in mice genetically deficient in IL-17R or in mice overexpressing a soluble IL-17R. IL-17R–deficient mice were exquisitely sensitive to intranasal K. pneumoniae with 100% mortality after 48 h compared with only 40% mortality in controls. IL-17R knockout (KO) mice displayed a significant delay in neutrophil recruitment into the alveolar space, and had greater dissemination of K. pneumoniae compared with control mice. This defect was associated with a significant reduction in steady-state levels of G-CSF and macrophage inflammatory protein (MIP)-2 mRNA and protein in the lung in response to the K. pneumoniae challenge in IL-17R KO mice. Thus, IL-17R signaling is critical for optimal production of G-CSF and MIP-2 and local control of pulmonary K. pneumoniae infection. These data support impaired IL-17R signaling as a potential mechanism by which deficiency of CD4 lymphocytes predisposes to bacterial pneumonia.

scholarly journals Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis

2021 ◽  
Vol 22 (23) ◽  
pp. 12923
Author(s):  
Zhiyi Ding ◽  
Feifei Du ◽  
Richard Garland Averitt V ◽  
Gabriel Jakobsson ◽  
Carl-Fredrik Rönnow ◽  
...  
Keyword(s):  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Abdominal Sepsis ◽  
Neutrophil Activation ◽  
Neutrophil Recruitment ◽  
Lung Damage ◽  
Edema Formation ◽  
Chemokine Production ◽  
Activated Complex

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.

scholarly journals Blockade of Indoleamine 2,3-Dioxygenase Reduces Mortality from Peritonitis and Sepsis in Mice by Regulating Functions of CD11b+Peritoneal Cells

2014 ◽  
Vol 82 (11) ◽  
pp. 4487-4495 ◽  
Author(s):  
Masato Hoshi ◽  
Yosuke Osawa ◽  
Hiroyasu Ito ◽  
Hirofumi Ohtaki ◽  
Tatsuya Ando ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Cecal Ligation ◽  
Bacterial Count ◽  
Inhibitory Effect ◽  
Chemokine Production ◽  
Bacterial Peritonitis ◽  
Indoleamine 2,3 Dioxygenase ◽  
Peritoneal Cells ◽  
Bone Marrow Derived Cells

ABSTRACTIndoleamine 2,3-dioxygenase-1 (Ido), which catalyzes the first and limiting step of tryptophan catabolism, has been implicated in immune tolerance. However, the roles of Ido in systemic bacterial infection are complicated and remain controversial. To explore this issue, we examined the roles of Ido in bacterial peritonitis and sepsis after cecal ligation and puncture (CLP) in mice by using the Ido inhibitor 1-methyl-d,l-tryptophan (1-MT), by comparing Ido+/+and Ido−/−mice, or by using chimeric mice in which Ido in the bone marrow-derived cells was deficient. Ido expression in the peritoneal CD11b+cells and its metabolitel-kynurenine in the serum were increased after CLP. 1-MT treatment or Ido deficiency, especially in bone marrow-derived cells, reduced mortality after CLP. Compared to Ido+/+mice, Ido−/−mice showed increased recruitment of neutrophils and mononuclear cells into the peritoneal cavity and a decreased bacterial count in the blood accompanied by increased CXCL-2 and CXCL-1 mRNA in the peritoneal cells. Ido has an inhibitory effect on LPS-induced CXCL-2 and CXCL-1 production in cultured peritoneal cells. These findings indicate that inhibition of Ido reduces mortality from peritonitis and sepsis after CLP via recruitment of neutrophils and mononuclear cells by chemokine production in peritoneal CD11b+cells. Thus, blockade of Ido plays a beneficial role in host protection during bacterial peritonitis and sepsis.

scholarly journals 11β-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI

2017 ◽  
Vol 233 (3) ◽  
pp. 315-327 ◽  
Author(s):  
Katie J Mylonas ◽  
Neil A Turner ◽  
Sumia A Bageghni ◽  
Christopher J Kenyon ◽  
Christopher I White ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cardiac Fibroblasts ◽  
Neutrophil Recruitment ◽  
Host Cells ◽  
Injured Myocardium ◽  
Donor Bone Marrow ◽  
Initial Injury ◽  
Bone Marrow Derived Cells ◽  
Host Myocardium

We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1−/−) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in ‘host’ myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the myocardium of Hsd11b1−/− mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1−/− mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5. These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.

scholarly journals An Essential Role for Non–Bone Marrow–Derived Cells in Control ofPseudomonas aeruginosaPneumonia

2005 ◽  
Vol 33 (5) ◽  
pp. 470-475 ◽  
Author(s):  
Adeline M. Hajjar ◽  
Heidi Harowicz ◽  
H. Denny Liggitt ◽  
Pamela J. Fink ◽  
Christopher B. Wilson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Essential Role ◽  
Bone Marrow Derived Cells

STAT3-dependent CXC chemokine formation and neutrophil migration in streptococcal M1 protein-induced acute lung inflammation

2015 ◽  
Vol 308 (11) ◽  
pp. L1159-L1167 ◽  
Author(s):  
Songen Zhang ◽  
Rundk Hwaiz ◽  
Lingtao Luo ◽  
Heiko Herwald ◽  
Henrik Thorlacius
Keyword(s):  
Streptococcus Pyogenes ◽  
Lung Inflammation ◽  
Neutrophil Migration ◽  
Neutrophil Recruitment ◽  
Acute Lung Inflammation ◽  
Chemokine Production ◽  
Stat3 Signaling ◽  
M1 Protein ◽  
Cxc Chemokine

Streptococcus pyogenes cause infections ranging from mild pharyngitis to severe streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, it was hypothesized that STAT3 signaling might be involved in M1 protein-evoked lung inflammation. The STAT3 inhibitor, S3I-201, was administered to male C57Bl/6 mice before iv challenge with M1 protein. Bronchoalveolar fluid and lung tissue were harvested for quantification of STAT3 activity, neutrophil recruitment, edema, and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Levels of IL-6 and HMGB1 were determined in plasma. CXCL2-induced neutrophil chemotaxis was studied in vitro. Administration of S3I-201 markedly reduced M1 protein-provoked STAT3 activity, neutrophil recruitment, edema formation, and inflammatory changes in the lung. In addition, M1 protein significantly increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Treatment with S3I-201 had no effect on M1 protein-induced expression of Mac-1 on neutrophils. In contrast, inhibition of STAT3 activity greatly reduced M1 protein-induced formation of CXC chemokines in the lung. Interestingly, STAT3 inhibition markedly decreased plasma levels of IL-6 and HMGB1 in animals exposed to M1 protein. Moreover, we found that S3I-201 abolished CXCL2-induced neutrophil migration in vitro. In conclusion, these novel findings indicate that STAT3 signaling plays a key role in mediating CXC chemokine production and neutrophil infiltration in M1 protein-induced acute lung inflammation.

Sign in / Sign up

Export Citation Format

Share Document