Functional Replacement of Murine CXCR2 by Its Human Homologue in the Development of Atherosclerosis in LDLR Knockout Mice

Mihara, Katsuhiro; Spansier, Mirjam; Rooseboom, Martijn; Smit, Martin-Jan; Dokter, Wim H.A.

doi:10.1248/bpb.30.1231

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…As the overwhelming neutrophilic inflammation and intense CXCL1 and CXCL2 production seemed to be associated with the severity of IAV infection, we wondered if antagonism of the receptors for CXCL1 and CXCL2 would impact the course of infection. Of note, there is much evidence that mice express the human homolog of CXCR2, the chemokine receptor for CXCL-8, and other related chemokines ( 17 ). The murine receptor homolog for human CXCR1 has also been reported but its role in murine models of inflammation is poorly known ( 18 ).…”

Section: Resultsmentioning

confidence: 99%

“…The murine receptor homolog for human CXCR1 has also been reported but its role in murine models of inflammation is poorly known ( 18 ). Despite this potential controversy, the drug used, DF2162, has been reported to block both chemokine receptors in humans ( 17 ) and CXCL1-mediated migration of murine neutrophils (unpublished data). To investigate the role of CXCR1/2 during influenza infection, mice were infected with 1 × 10 4 PFU of IAV and then treated twice a day (from day 0—at the time of the infection—to day 5 post-infection) with DF2162 at a dose that efficiently decreased neutrophil numbers in the lungs of mice in another model of inflammation ( 16 ).…”

Section: Resultsmentioning

confidence: 99%

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CXCR1/2 Antagonism Is Protective during Influenza and Post-Influenza Pneumococcal Infection

et al. 2017

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RationaleInfluenza A infections are a leading cause of morbidity and mortality worldwide especially when associated with secondary pneumococcal infections. Inflammation is important to control pathogen proliferation but may also cause tissue injury and death. CXCR1/2 are chemokine receptors relevant for the recruitment of neutrophils. We investigated the role of CXCR1/2 during influenza, pneumococcal, and post-influenza pneumococcal infections.MethodsMice were infected with influenza A virus (IAV) or Streptococcus pneumoniae and then treated daily with the CXCR1/2 antagonist DF2162. To study secondary pneumococcal infection, mice were infected with a sublethal inoculum of IAV then infected with S. pneumoniae 14 days later. DF2162 was given in a therapeutic schedule from days 3 to 6 after influenza infection. Lethality, weight loss, inflammation, virus/bacteria counts, and lung injury were assessed.ResultsCXCL1 and CXCL2 were produced at high levels during IAV infection. DF2162 treatment decreased morbidity and this was associated with decreased infiltration of neutrophils in the lungs and reduced pulmonary damage and viral titers. During S. pneumoniae infection, DF2162 treatment decreased neutrophil recruitment, pulmonary damage, and lethality rates, without affecting bacteria burden. Therapeutic treatment with DF2162 during sublethal IAV infection reduced the morbidity associated with virus infection and also decreased the magnitude of inflammation, lung damage, and number of bacteria in the blood of mice subsequently infected with S. pneumoniae.ConclusionModulation of the inflammatory response by blocking CXCR1/2 improves disease outcome during respiratory influenza and pneumococcal infections, without compromising the ability of the murine host to deal with infection. Altogether, inhibition of CXCR1/2 may be a valid therapeutic strategy for treating lung infections caused by these pathogens, especially controlling secondary bacterial infection after influenza.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

CXCR1/2 Antagonism Is Protective during Influenza and Post-Influenza Pneumococcal Infection

et al. 2017

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“…To better understand the role of human CXCR2 in atherosclerosis, a hCXCR2 ϩ/ϩ Ldlr Ϫ/Ϫ mouse model was proposed, which-given the crossreactivity of murine ligands with hCXCR2 2 -would allow for testing novel pharmaceuticals designed to antagonize hCXCR2. 56 Numerous studies found that inflammatory biomarkers help to identify patients with stable CAD and acute coronary syndromes and is predictive for the development of CAD in high-risk patients. The role of chemokines as candidates for cardiovascular risk prediction has been appreciated, although it has not been validated in large clinical trials.…”

Section: Importance Of Cxcr2 In Endothelial Regenerationmentioning

confidence: 99%

Chemokines in Atherosclerosis

Zernecke

Shagdarsuren

Weber

2008

ATVB

346

220

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Abstract-The fundamental importance of chemokines for atherogenesis, progression, and destabilization of atherosclerotic plaques is now widely appreciated, but the degree of complexity, specificity, and cooperativity harnessed by these signal molecules to govern atherogenic cell recruitment and homeostasis is still being refined. Since the role of chemokines in atherosclerotic vascular disease has been reviewed in this journal, significant progress has been accomplished in defining the regulation of chemokine expression and function in atherosclerosis. In this update, we will highlight these recent developments, in particular the identification of components regulating the transcriptional machinery of the proatherogenic chemokine CCL5, distinct roles of its receptors CCR1 and CCR5 in plaque formation and immunobalance, and differential site-and stage-specific effects of T cell-activating chemokines and their receptors, eg, CXCL10 and CXCR3. The contribution of the transmembrane chemokines CX 3 CL1 and CXCL16 with their respective receptors CX 3 CR1 and CXCR6 in the recruitment of T cell and monocyte subsets and shear-mediated plaque modulation will be discussed. Finally, the role of CXCR2 and CXCR4, their respective ligands CXCL1 and CXCL12, and the noncanonical dual agonist MIF in atheroprogression will be dissected.

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“…In aortic plaques from LDLR −/− mice, the secretion of CXCL2 (MIP‐2) and CXCL1 (KC), both endogenous ligands of CXCR2, were significantly increased compared with control animals (Mihara et al, 2007). Moreover, the administration of the CXCR2 antagonist SB225002 to ApoE −/− mice was able to decrease significantly aorta plaque formation (Wu et al, 2011).…”

Section: Cardiovascular Systemmentioning

confidence: 99%

The oxysterome and its receptors as pharmacological targets in inflammatory diseases

Guillemot-Legris

Muccioli

2021

British J Pharmacology

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Note: This table presents the main endogenous oxysterols and their receptors. The pharmacological parameters are presented as pK i (i.e., Àlog Ki), pEC 50 (i.e., Àlog EC 50 ) or pIC 50 (i.e., Àlog IC 50 ) depending on the data reported in the literature. Abbreviations: GPR17, GPCR 17; GPR183, GPCR 183 (also known as EBI2); GR, glucocorticoid receptor; LBD, ligand-binding domain; LXR, liver X receptor; ND, not determined; NMDAR, N-methyl-D-aspartate receptor; ROR, retinoic acid receptor-related orphan receptor; SERM, selective oestrogen receptor modulator. a OCDO and glucocorticoids act through GR but have different mechanisms of action on GR transcriptional targets (Voisin et al., 2017). b The functional activity is unclear as different results are obtained depending on the construct used to measure RORγ activity (LBD vs. full-length RORγ) (Soroosh et al., 2014).

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Functional Replacement of Murine CXCR2 by Its Human Homologue in the Development of Atherosclerosis in LDLR Knockout Mice

Cited by 6 publications

References 26 publications

CXCR1/2 Antagonism Is Protective during Influenza and Post-Influenza Pneumococcal Infection

CXCR1/2 Antagonism Is Protective during Influenza and Post-Influenza Pneumococcal Infection

Chemokines in Atherosclerosis

The oxysterome and its receptors as pharmacological targets in inflammatory diseases

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