A role for apoptosis in the control of neutrophil homeostasis in the circulation: insights from CD18-deficient mice

Weinmann, Pamela; Scharffetter‐­Kochanek, Karin; Forlow, S. Bradley; Peters, Thorsten; Walzog, Barbara

doi:10.1182/blood-2002-01-0239

Cited by 67 publications

(49 citation statements)

References 26 publications

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“…The neutrophilia seen in these mice is not due to the passive accumulation of neutrophils in the vasculature, nor due to alterations in the marginating pool found in the lung, but is primarily caused by increased granulopoiesis (37,41). A reduction in neutrophil apoptosis may also contribute to neutrophilia in Itgb2 Ϫ/Ϫ mice (42). Previous studies have shown that IL-17A can act directly on BM stromal cells to produce G-CSF, up-regulate the cell surface expression of stem cell factor, as well as stimulate myeloid progenitor cell proliferation (36).…”

Section: Discussionmentioning

confidence: 99%

IL-23 Is Required for Neutrophil Homeostasis in Normal and Neutrophilic Mice

Smith

Zarbock

Stark

et al. 2007

The Journal of Immunology

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IL-23 is secreted by macrophages and dendritic cells in response to microbial products and inflammatory cytokines. IL-23 is a heterodimer composed of the unique IL-23p19 subunit linked to the common p40 subunit that it shares with IL-12. IL-23 is implicated in autoimmune diseases, where it supports the expansion of IL-17A-producing CD4+ Th17 cells. IL-23 also regulates granulopoiesis in a neutrostat regulatory feedback loop through IL-17A-producing neutrophil regulatory (Tn) cells, most of which express γδ TCR. This homeostatic system is disrupted in mice lacking adhesion molecules like β2-integrins (Itgb2−/−) which have defective neutrophil trafficking and neutrophilia. To test the role of IL-23 in the homeostatic regulation of circulating neutrophil numbers, we measured blood neutrophil numbers in p40-deficient (IL12b−/−) mice and found them reduced compared with wild-type mice. IL12b−/−Itgb2−/− mice, lacking β2-integrins, IL-12, and IL-23 showed significantly blunted neutrophilia compared with Itgb2−/− mice. Treatment of both IL12b−/− and IL12b−/−Itgb2−/− mice with IL-23, but not IL-12, restored circulating neutrophil counts. Serum levels of IL-17A were readily detectable in Itgb2−/− mice, but not in IL12b−/−Itgb2−/− mice, suggesting that IL-17A production is reduced when IL-23 is absent. Similarly, tissue mRNA expression of IL-17A was reduced in IL12b−/−Itgb2−/−mice compared with Itgb2−/− controls. The total number of CD3+ IL-17A-producing Tn cells were significantly reduced in the spleen and lamina propria of IL12b−/−Itgb2−/− mice, with the largest reduction found in γδ+ T cells. Our results suggest a prominent role of IL-23 in the regulation of granulopoiesis and the prevalence of IL-17A-producing Tn cells.

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Section: Discussionmentioning

confidence: 99%

IL-23 Is Required for Neutrophil Homeostasis in Normal and Neutrophilic Mice

Smith

Zarbock

Stark

et al. 2007

The Journal of Immunology

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“…Thus, increased neutrophil numbers observed in both α4Δ/Δ and β2-/-mice at 96 hours post TG injection may suggest either delay in apoptosis, impaired clearance, or sustained neutrophil recruitment. Involvement of both α4 and β2 integrins in regulating apoptosis and/or clearing of apoptotic cells have been demonstrated; deficiency in β2 integrins leads to a delay in neutrophil apoptosis and their subsequent accumulation in the peritoneum [40,41], while α4 integrin on apoptotic cells assist in their phagocytosis [42]. Thus, absence of α4 integrins may affect clearance of α4Δ/Δ neutrophils, thereby resulting in increased neutrophil presence in the peritoneum.…”

Section: Discussionmentioning

confidence: 99%

Unique and redundant roles of α4 and β2 integrins in kinetics of recruitment of lymphoid vs myeloid cell subsets to the inflamed peritoneum revealed by studies of genetically deficient mice

Ulyanova

Priestley

Banerjee

et al. 2007

Experimental Hematology

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OBJECTIVE-Leukocyte recruitment to inflammatory sites is a prominent feature of acute and chronic inflammation. Instrumental in this process is the coordinated upregulation of leukocyte integrins (among which α4β1 and β2 integrins are major players) and their cognate receptors in inflamed tissues. To avoid the ambiguity of previous short-term antibody-based studies and to allow for long-term observation, we used genetically deficient mice to compare roles of α4 and β2 integrins in leukocyte trafficking.METHODS-Aseptic peritonitis was induced in α4 or β2 integrin-deficient (conditional and conventional knockouts, respectively) and control mice, and recruitment of major leukocyte subsets to the inflamed peritoneum was followed for up to 4 days. RESULTS-Despite normal chemokine levels in the peritoneum and adequate numbers, optimal recruitment of myeloid cells was impaired in both α4-and β2-deficient mice. Furthermore, clearance of recruited neutrophils and macrophages was delayed in these mice. Lymphocyte migration to the peritoneum in the absence of α4 integrins was drastically decreased, both at steady state and during inflammation, a finding consistent with impaired lymphocyte in vitro adhesion and signaling. By contrast, in the absence of β2 integrins, defects in lymphocyte recruitment were only evident when peritonitis was established.CONCLUSIONS-Our data with concurrent use of genetic models of integrin deficiency reveal non-redundant functions of α4 integrins in lymphocyte migration to the peritoneum and further refine specific roles of α4 and β2 integrins concerning trafficking and clearance of other leukocyte subsets at homeostasis and during inflammation.

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“…A series of molecular events is involved in PMN apoptosis and is dependent on numerous environmental factors (9). Recent reports have demonstrated that intracellular mechanisms, which determine the lifetime of PMN critically involve the differential expression of the Bcl-2 family members Bax-a and Bcl-Xi, that control the apoptotic machinery of PMN in vivo (15,69). The environmental factors in our coculture model that might be involved in regulating pro-and antiapoptotic genes of PMN in close contact with airway epithelial cells await further attention.…”

Section: Discussionmentioning

confidence: 99%

Adherence of airway neutrophils and inflammatory response are increased in CF airway epithelial cell-neutrophil interactions

Tabary¹,

Corvol²,

Boncoeur³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Persistent presence of PMN in airways is the hallmark of CF. Our aim was to assess PMN adherence, percentage of apoptotic airway PMN (aPMN), and IL-6 and IL-8 production when aPMN are in contact with airway epithelial cells. Before coculture, freshly isolated CF aPMN have greater spontaneous and TNF-α-induced apoptosis compared with blood PMN from the same CF patients and from aPMN of non-CF patients. We then examined cocultures of PMN isolated from CF and non-CF airways with bronchial epithelial cells bearing mutated cftr compared with cftr-corrected bronchial epithelial cells. After 18-h coculture, the number of CF aPMN adhered on cftr-deficient bronchial epithelial cells was 2.3-fold higher compared with the coculture of non-CF aPMN adhered on cftr-corrected bronchial epithelial cells. The percentage of CF apoptotic aPMN (9.5 ± 0.2%) adhered on cftr-deficient bronchial epithelial cells was similar to the percentage of non-CF apoptotic aPMN adhered on cftr-corrected bronchial epithelial cells (10.3 ± 0.7%). IL-6 and IL-8 levels were enhanced 6.5- and 2.9-fold, respectively, in coculture of CF aPMN adhered on cftr-deficient bronchial epithelial cells compared with coculture of non-CF aPMN adhered on cftr-corrected bronchial epithelial cells. Moreover, blocking surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on cftr-deficient bronchial epithelial cells with specific MAbs inhibited the adherence of CF aPMN by 64, 51, and 50%, respectively. Our data suggest that in CF patients a high number of nonapoptotic PMN adhered on airway epithelium associated with elevated IL-6 and IL-8 levels may contribute to sustained and exaggerated inflammatory response in CF airways.

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A role for apoptosis in the control of neutrophil homeostasis in the circulation: insights from CD18-deficient mice

Cited by 67 publications

References 26 publications

IL-23 Is Required for Neutrophil Homeostasis in Normal and Neutrophilic Mice

IL-23 Is Required for Neutrophil Homeostasis in Normal and Neutrophilic Mice

Unique and redundant roles of α4 and β2 integrins in kinetics of recruitment of lymphoid vs myeloid cell subsets to the inflamed peritoneum revealed by studies of genetically deficient mice

Adherence of airway neutrophils and inflammatory response are increased in CF airway epithelial cell-neutrophil interactions

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