Functional α4-integrin: A newly identified pathway of neutrophil recruitment in critically ill septic patients

Ibbotson, Geoffrey C.; Doig, Christopher J.; Kaur, Jaswinder; Gill, Varinder; Ostrovsky, Lena; Fairhead, Todd; Kubes, Paul

doi:10.1038/86539

Cited by 132 publications

(103 citation statements)

References 37 publications

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“…The inhibition of neutrophil adherence to OB by the antiCD49d antibody suggested that CD49d was involved in the adhesion. This is in agreement with the increased expression of CD49d by neutrophils, as previously reported, 29 and its lack of expression by OBs. In the experimental conditions Figure 7 Schematic representation of pathological sequences associated with MSU deposits in bone.…”

Section: Discussionsupporting

confidence: 80%

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Osteoblast retraction induced by adherent neutrophils promotes osteoclast bone resorption: implication for altered bone remodeling in chronic gout

Allaeys

Rusu

Picard

et al. 2011

Laboratory Investigation

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Bone destruction in chronic gout is correlated with deposits of monosodium urate (MSU) crystals. Bone with MSU tophi were histopathologically shown to have altered remodeling and cellular distribution. We investigated the impact of neutrophils in bone remodeling associated with MSU and demonstrated that neutrophils, through elastase localized at their surface, induced retraction of confluent osteoblasts (OBs) previously layered on calcified matrix. This OB retraction allowed osteoclasts to resorb cell-free areas of the matrix. This neutrophil effect was concentration dependent and time dependent and required direct contact with OBs. Exposure of OBs to MSU greatly promoted neutrophil adherence to OBs. Neutrophil membrane at the contact zone with OBs showed concentrated fluorescence of dye PKH-67, indicating a cellular contact. Neutrophil-OB interaction increased the survival of neutrophils, reduced their release of lactoferrin in presence of MSU and did not change OB-mediated mineralization. The adhesion of neutrophils to OBs was heterotypic through neutrophil CD29/CD49d and OB-fibronectin peptide CS1. Leukotriene B 4 (LTB 4 ) and platelet-activating factor (PAF) were also involved in neutrophil adherence to OBs, as shown by the blocking effect of selective LTB 4 and PAF receptor antagonists, and a cytosolic phospholipase A 2a (cPLA 2a ) inhibitor. Blockade of CD49d/CS1 and inhibition of the cPLA 2a had subadditive effects, reducing by 60% the adherence of neutrophils to OBs. Taken together, these data showed that neutrophil adhesion to MSU-activated OBs was mediated by the b 1 integrin CD29/CD49d-fibronectin peptide CS1 receptors and cPLA 2a -derived metabolites and impacts on OB and osteoclast functions. These interactions could be involved in the local bone remodeling process of gout.Laboratory Investigation (2011) 91, 905-920;

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Section: Discussionsupporting

confidence: 80%

“…Adherent neutrophils express the b 1 integrin CD29/CD49d, and various inflammatory conditions increase neutrophil expression of the subunit CD49d. 14,29,30 Neutrophils also express the b 1 integrin subunit CD49e. 31 CD29 and ICAM-1 were expressed by OBs, while CD49d and CD49e were not ( Table 1).…”

Section: Integrin Involvement In Neutrophil Adhesion To Obsmentioning

confidence: 99%

Osteoblast retraction induced by adherent neutrophils promotes osteoclast bone resorption: implication for altered bone remodeling in chronic gout

Allaeys

Rusu

Picard

et al. 2011

Laboratory Investigation

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“…These results are consistent with experimental and clinical data showing that, during inflammatory episodes, circulating neutrophils express low levels of L-selectin and elevated levels of CD11b and CD49d. 1,[12][13][14][15][16] Further, the same changes in adhesion molecule expression have previously been reported following stimulation of neutrophils with chemotactic factors in vitro. 23,24 Therefore, using the in situ perfusion system of the rat femoral bone marrow we sought to investigate the functional significance of these changes with respect to the mobilization process.…”

Section: Discussionsupporting

confidence: 55%

“…23,[29][30][31][32] Expression of CD49d on neutrophils is up-regulated in vivo during specific inflammatory reactions and in vitro when neutrophils migrate in response to chemoattractants. 12,13,23 In this study we report that expression of CD49d is significantly increased as neutrophils are mobilized from the bone marrow. Moreover, we show here, for the first time, that neutrophil mobilization in response to an inflammatory stimulus, MIP-2, is CD49d dependent.…”

Section: Discussionmentioning

confidence: 77%

“…Neutrophils mobilized during inflammatory reactions express reduced levels of CD62L (L-selectin) and elevated levels of CD11b (Mac1) and CD49d (very late antigen 4 [VLA4]), suggesting that these molecules may play a functional role in the release process. 1,[12][13][14][15][16] In this study we have examined whether the shedding of L-selectin is necessary for neutrophil release from the bone marrow and investigated the role of CD18 (␤2 integrin subunit) and CD49d integrins in this process. Our results highlight the fact that the molecular mechanisms regulating neutrophil mobilization from the bone marrow are distinct from those involved in neutrophil extravasation from the blood into tissues.…”

Section: Introductionmentioning

confidence: 99%

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The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner

Burdon

Martin

Rankin

2005

Blood

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The acute release of neutrophils from the bone marrow is a critical step in their trafficking to sites of inflammation. This process is stimulated by systemically acting inflammatory mediators, such as the CXC chemokines. In this study we have used a novel in situ perfusion system of the rat femoral bone marrow to directly investigate the role of specific adhesion molecules in chemokine-stimulated neutrophil mobilization. We show here that neutrophils mobilized in response to rat macrophage inflammatory protein-2 (MIP-2) shed L-selectin and expressed significantly higher levels of CD11b and CD49d. However, inhibition of L-selectin sheddase activity with KD-IX-73-4 had no effect on the number of neutrophils mobilized in response to rat MIP-2. Blockade of CD18, using a neutralizing monoclonal antibody (mAb), did not inhibit neutrophil mobilization but unexpectedly increased the rate and number of neutrophils released from the bone marrow in response to chemokine, suggesting that CD18 could play a role in neutrophil retention within the bone marrow. Blockade of CD49d using either a selective mAb or a specific antagonist resulted in a dramatic inhibition (> 75%) of the chemokine-stimulated neutrophil mobilization from the bone marrow. These data reveal contrasting roles for CD18 and CD49d in the retention and release of neutrophils from the bone marrow. (Blood. 2005;105:2543-2548)

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The role of selectins and integrins in adenovirus vector-induced neutrophil recruitment to the liver

Muruve

Collins

et al. 2002

Eur. J. Immunol.

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Adenovirus vectors for human gene therapy induce early host inflammatory responses in transduced tissues that limit gene transfer efficiency and can result in significant morbidity. The present study aimed to elucidate the cellular mechanisms underlying the acute inflammation induced by adenovirus vectors in the liver. Leukocyte rolling and adhesion in response to an intravenously administered adenovirus vector was examined by intravital microscopy in mouse liver. Adenovirus vectors significantly increased leukocyte rolling and adhesion in the postsinusoidal venules within minutes of transduction. Unlike other inflammatory states in the liver, no leukocyte retention was seen in the sinusoids in response to adenovirus vector administration. Inhibition of P‐selectin, α4‐integrin, and E‐selectin was necessary to completely block leukocyte rolling and subsequent adhesion. The administration of an anti‐α4‐integrin antibody alone significantly reduced leukocyte adhesion. In contrast, adenovirus vector‐induced leukocyte adhesion was unchanged in CD18‐knockout mice. Depletion of circulating neutrophils eliminated leukocyte rolling and adhesion in response to adenovirus vector transduction in the liver. In conclusion, adenovirus vectors induce rapid neutrophil‐mediated inflammation in the post‐sinusoidal venules by selectins and α4‐integrin but surprisingly not by CD18.

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Functional α4-integrin: A newly identified pathway of neutrophil recruitment in critically ill septic patients

Cited by 132 publications

References 37 publications

Osteoblast retraction induced by adherent neutrophils promotes osteoclast bone resorption: implication for altered bone remodeling in chronic gout

Osteoblast retraction induced by adherent neutrophils promotes osteoclast bone resorption: implication for altered bone remodeling in chronic gout

The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner

The role of selectins and integrins in adenovirus vector-induced neutrophil recruitment to the liver

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