α4 and β2 integrins have nonredundant roles for asthma development, but for optimal allergen sensitization only α4 is critical

Banerjee, Ena Ray; Jiang, Yuanchun; Henderson, William R.; Scott, Linda M.; Papayannopoulou, Thalia

doi:10.1016/j.exphem.2007.01.052

Cited by 31 publications

(54 citation statements)

References 53 publications

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“…Our results are in agreement with previously reported observations in chimeric mice in which α4Δ/Δ lymphocytes did not migrate into the inflamed peritoneum [19]. However, the dependence of lymphocyte recruitment on α4 integrin is also a tissuespecific phenomenon; recruitment of lymphocytes to brain tissue is mainly dependent on α4 integrin [43], whereas their migration to inflamed lungs and airways is mediated by both α4 and β2 integrins [11,44,45], and migration to inflamed skin depends exclusively upon β2 integrin engagement [46].…”

Section: Discussionsupporting

confidence: 83%

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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Section: Discussionsupporting

confidence: 83%

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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“…This idea is consistent with in vivo studies supporting the involvement of ␣ 4 ␤ 1 in eosinophil appearance in the airway and with in vitro studies showing the involvement of both ␤ 1 and ␤ 2 integrins in eosinophil transendothelial migration (22,(51)(52)(53)(54)(55)(56). The evidence for involvement of both ␣ 4 ␤ 1 and ␤ 2 integrins in eosinophil migration in vivo is further strengthened by a recent report that eosinophil recruitment to airway after Ag challenge was severely attenuated in both a conditional ␣ 4 integrin knockout mouse and a ␤ 2 -deficient mouse (57). Finally, ␣ D expression and ␤ 1 activation on blood eosinophils as well as ␤ 2 and ␣ M expression and ␤ 2 activation on BAL eosinophils after segmental Ag challenge all correlated with the magnitude of the late-phase fall in FEV 1 in response to whole-lung Ag challenge.…”

Section: Discussionmentioning

confidence: 50%

Up-Regulation and Activation of Eosinophil Integrins in Blood and Airway after Segmental Lung Antigen Challenge

Johansson¹,

Kelly

Busse

et al. 2008

The Journal of Immunology

117

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We hypothesized that there are clinically relevant differences in eosinophil integrin expression and activation in patients with asthma. To evaluate this, surface densities and activation states of integrins on eosinophils in blood and bronchoalveolar lavage (BAL) of 19 asthmatic subjects were studied before and 48 h after segmental Ag challenge. At 48 h, there was increased expression of αD and the N29 epitope of activated β1 integrins on blood eosinophils and of αM, β2, and the mAb24 epitope of activated β2 integrins on airway eosinophils. Changes correlated with the late-phase fall in forced expiratory volume in 1 s (FEV1) after whole-lung inhalation of the Ag that was subsequently used in segmental challenge and were greater in subjects defined as dual responders. Increased surface densities of αM and β2 and activation of β2 on airway eosinophils correlated with the concentration of IL-5 in BAL fluid. Activation of β1 and β2 on airway eosinophils correlated with eosinophil percentage in BAL. Thus, eosinophils respond to an allergic stimulus by activation of integrins in a sequence that likely promotes eosinophilic inflammation of the airway. Before challenge, β1 and β2 integrins of circulating eosinophils are in low-activation conformations and αDβ2 surface expression is low. After Ag challenge, circulating eosinophils adopt a phenotype with activated β1 integrins and up-regulated αDβ2, changes that are predicted to facilitate eosinophil arrest on VCAM-1 in bronchial vessels. Finally, eosinophils present in IL-5-rich airway fluid have a hyperadhesive phenotype associated with increased surface expression of αMβ2 and activation of β2 integrins.

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“…Therefore, we hypothesized that the overabundance of Itgα4 on the surface of cKO HSPCs might act to immobilize HSPC clusters by increased adhesion to the vascular wall, preventing release into the circulation and subsequent colonization of the FL. To test the hypothesis, a neutralizing antibody against Itgα4 (anti-Itgα4) 48 or non-specific (control) IgG was injected into pregnant mice at E9.5-E11.5, and HSPC clusters in cKO AGMs were examined at E12.0 (Fig. 9a).…”

Section: Resultsmentioning

confidence: 99%

“…This is analogous to the inflammatory process by which leukocytes secreting LTB4 increase their adhesion to the vascular wall 39, 45, 58–61 . Therapies to block adhesion molecules, such as α4 Itg, are found to be effective for various inflammatory conditions, such as asthma, multiple sclerosis, and inflammatory bowel disease 48, 62, 63 .…”

Section: Discussionmentioning

confidence: 99%

Let-7 microRNA-dependent control of leukotriene signaling regulates the transition of hematopoietic niche in mice

et al. 2017

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Hematopoietic stem and progenitor cells arise from the vascular endothelium of the dorsal aorta and subsequently switch niche to the fetal liver through unknown mechanisms. Here we report that vascular endothelium-specific deletion of mouse Drosha (Drosha cKO), an enzyme essential for microRNA biogenesis, leads to anemia and death. A similar number of hematopoietic stem and progenitor cells emerge from Drosha-deficient and control vascular endothelium, but Drosha cKO-derived hematopoietic stem and progenitor cells accumulate in the dorsal aorta and fail to colonize the fetal liver. Depletion of the let-7 family of microRNAs is a primary cause of this defect, as it leads to activation of leukotriene B4 signaling and induction of the α4β1 integrin cell adhesion complex in hematopoietic stem and progenitor cells. Inhibition of leukotriene B4 or integrin rescues maturation and migration of Drosha cKO hematopoietic stem and progenitor cells to the fetal liver, while it hampers hematopoiesis in wild-type animals. Our study uncovers a previously undefined role of innate leukotriene B4 signaling as a gatekeeper of the hematopoietic niche transition.

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α4 and β2 integrins have nonredundant roles for asthma development, but for optimal allergen sensitization only α4 is critical

Cited by 31 publications

References 53 publications

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

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

Up-Regulation and Activation of Eosinophil Integrins in Blood and Airway after Segmental Lung Antigen Challenge

Let-7 microRNA-dependent control of leukotriene signaling regulates the transition of hematopoietic niche in mice

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