| 1. |
- Abonia, J Pablo, et al.
(författare)
-
Alpha-4 integrins and VCAM-1, but not MAdCAM-1, are essential for recruitment of mast cell progenitors to the inflamed lung
- 2006
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 108:5, s. 1588-1594
-
Tidskriftsartikel (refereegranskat)abstract
- Normal mouse lungs lack appreciable numbers of mast cells (MCs) or MC progenitors (MCp's), yet the appearance of mature MCs in the tracheobronchial epithelial surface is a characteristic of allergic, T-cell-dependent pulmonary inflammation. We hypothesized that pulmonary inflammation would recruit MCp's to inflamed lungs and that this recruitment would be regulated by distinct adhesion pathways. Ovalbumin-sensitized and challenged mice had a greater than 28-fold increase in the number of MCp's in the lungs. In mice lacking endothelial vascular cell adhesion molecule 1 (VCAM-1) and in wild-type mice administered blocking monoclonal antibody (mAb) to VCAM-1 but not to mucosal addressin CAM-1 (MadCAM-1), recruitment of MCp's to the inflamed lung was reduced by greater than 75%. Analysis of the integrin receptors for VCAM-1 showed that in beta7 integrin-deficient mice, recruitment was reduced 73% relative to wild-type controls, and in either BALB/c or C57BL/6 mice, mAb blocking of alpha4, beta1, or beta7 integrins inhibited the recruitment of MCp's to the inflamed lung. Thus, VCAM-1 interactions with both alpha4beta1 and alpha4beta7 integrins are essential for the recruitment and expansion of the MCp populations in the lung during antigen-induced pulmonary inflammation. Furthermore, the MCp is currently unique among inflammatory cells in its partial dependence on alpha4beta7 integrins for lung recruitment.
|
|
| 2. |
- Collington, Sarah J, et al.
(författare)
-
The role of the CCL2/CCR2 axis in mouse mast cell migration in vitro and in vivo
- 2010
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 184:11, s. 6114-6123
-
Tidskriftsartikel (refereegranskat)abstract
- Tissue-resident mast cells (MCs) are important in allergic diseases. In a mouse model of allergic airways inflammation, an increase in peribronchiolar MCs was associated with increased concentrations of the chemokine CCL2 in lung lavage. MC progenitors (MCps) arising in bone marrow (BM) are recruited to tissues by transendothelial migration, and we found that CCL2 is chemotactic for MCps in freshly isolated BM in vitro. Immature, but not mature, BM-derived MCs migrated in response to CCL2 when cultured in IL-3+stem cell factor (SCF) but not when cultured in IL-3 alone. However, the cells under both culture conditions expressed mRNA for CCR2, the receptor for CCL2, and bound the radiolabeled chemokine with similar affinities, highlighting SCF as a key mediator in coupling CCR2 to downstream events, culminating in chemotaxis. Immature BM-derived MCs from IL-3 +SCF cultures, when administered i.v., accumulated at skin sites injected with CCL2 in vivo. MCp recruitment to the allergen-sensitized/challenged lung was significantly reduced in CCR2(-/-) and CCL2(-/-) mouse strains. However, reconstitution studies of sublethally irradiated and BM-reconstituted mice indicated that BM cells and stromal elements could provide CCL2, whereas the CCR2 function resided with stromal elements rather than BM cells. These experiments revealed a new function of SCF in chemokine receptor coupling, but they suggest a complex role of the CCL2/CCR2 axis in recruiting MCps during pulmonary inflammation.
|
|
| 3. |
|
|
| 4. |
- Cui, Yue, et al.
(författare)
-
Mouse Mast Cell Protease-6 and MHC Are Involved in the Development of Experimental Asthma
- 2014
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 193:10, s. 4783-4789
-
Tidskriftsartikel (refereegranskat)abstract
- Allergic asthma is a complex disease with a strong genetic component where mast cells play a major role by the release of proinflammatory mediators. In the mouse, mast cell protease-6 (mMCP-6) closely resembles the human version of mast cell tryptase, beta-tryptase. The gene that encodes mMCP-6, Tpsb2, resides close by the H-2 complex (MHC gene) on chromosome 17. Thus, when the original mMCP-6 knockout mice were backcrossed to the BALB/c strain, these mice were carrying the 129/Sv haplotype of MHC (mMCP-6(-/-)/H-2bc). Further backcrossing yielded mMCP-6(-/-) mice with the BALB/c MHC locus. BALB/c mice were compared with mMCP-6(-/-) and mMCP-6(-/-)/H-2bc mice in a mouse model of experimental asthma. Although OVA-sensitized and challenged wild type mice displayed a striking airway hyperresponsiveness (AHR), mMCP-6(-/-) mice had less AHR that was comparable with that of mMCP-6(-/-)/H-2bc mice, suggesting that mMCP-6 is required for a full-blown AHR. The mMCP-6(-/-)/H-2bc mice had strikingly reduced lung inflammation, IgE responses, and Th2 cell responses upon sensitization and challenge, whereas the mMCP-6(-/-) mice responded similarly to the wild type mice but with a minor decrease in bronchoalveolar lavage eosinophils. These findings suggest that inflammatory Th2 responses are highly dependent on the MHC-haplotype and that they can develop essentially independently of mMCP-6, whereas mMCP-6 plays a key role in the development of AHR.
|
|
| 5. |
- Groschwitz, Katherine R., et al.
(författare)
-
Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism
- 2009
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:52, s. 22381-22386
-
Tidskriftsartikel (refereegranskat)abstract
- Altered intestinal barrier function is postulated to be a central predisposing factor to intestinal diseases, including inflammatory bowel diseases and food allergies. However, the mechanisms involved in maintaining homeostatic intestinal barrier integrity remain undefined. In this study, we demonstrate that mice deficient in mast cells (Kit(W-sh/W-sh) [Wsh]) or mast cell chymase (Mcpt4(-/-)) have significantly decreased basal small intestinal permeability compared with wild-type (WT) mice. Altered intestinal barrier function was linked to decreased intestinal epithelial cell migration along the villus/crypt axis, altered intestinal morphology, and dysregulated claudin-3 crypt expression. Remarkably, engraftment of Wsh mice with WT but not Mcpt4(-/-) mast cells restored intestinal epithelial cell migration, morphology, and intestinal epithelial barrier function. Collectively, these findings identify a mechanism by which mast cells regulate homeostatic intestinal epithelial migration and barrier function.
|
|
| 6. |
- Hallgren, Jenny, et al.
(författare)
-
Granule maturation in mast cells : Histamine in control
- 2014
-
Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 44:1, s. 33-36
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Mast cells are derived from committed progenitors that originate in the BM. They mature into histochemically distinguishable, metachromatic mast cells containing numerous cytoplasmic secretory granules. Accumulating evidence demonstrates that mast cell granule maturation is very tightly regulated by many factors including different granule components such as proteoglycans. In this issue of the European Journal of Immunology, Nakazawa et al. [Eur. J. Immunol. 2014. 44: 204–214] highlight a role for mast cell derived histamine as another factor critical for mast cell maturation. Using histidine decarboxylase (HDC) deficient mice that are unable to make histamine, they show poorly formed secretory granules and decreased secretory granule protease expression in peritoneal mast cells. Co-culturing BM-derived mast cells with fibroblasts normally drives granule maturation, but HDC-deficient BM-derived mast cells fail to do so. Exogenously provided histamine partly restores granule differentiation as evidenced by increased tryptase and chymase activity, and this is histamine receptor type H4-dependent. However, H4-deficient mice have intact granule formation in peritoneal mast cells, suggesting that when HDC is functional, the intrinsic histamine production is sufficient for most granule maturation processes and H4 is dispensable. This study highlights the role of histamine in the regulation of mast cell maturation, although the cytosolic target remains unknown.
|
|
| 7. |
- Hallgren, Jenny, et al.
(författare)
-
Mast cell progenitor trafficking and maturation
- 2011
-
Ingår i: Advances in Experimental Medicine and Biology. - Boston, MA : Springer US. - 0065-2598 .- 2214-8019. ; 716:Section II, s. 14-28
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Mast cells are derived from the hematopoietic progenitors found in bone marrow and spleen. Committed mast cell progenitors are rare in bone marrow suggesting they are rapidly released into the blood where they circulate and move out into the peripheral tissues. This migration is controlled in a tissue specific manner. Basal trafficking to the intestine requires expression of alpha 4 beta 7 integrin and the chemokine receptor CXCR2 by the mast cell progenitors and expression of MAdCAM-1 and VCAM-1 in the intestinal endothelium; and is also controlled by dendritic cells expressing the transcriptional regulatory protein T-bet. None of these play a role in basal trafficking to the lung. With the induction of allergic inflammation in the lung, there is marked recruitment of committed mast cell progenitors to lung and these cells must express alpha 4 beta 7 and alpha 4 beta 1 integrins. Within the lung there is a requirement for expression of VCAM-1 on the endothelium that is regulated by CXCR2, also expressed on the endothelium. There is a further requirement for expression of the CCR2/CCL2 pathways for full recruitment of the mast cell progenitors to the antigen-inflamed lung.
|
|
| 8. |
- Hallgren, Jenny, et al.
(författare)
-
Pathways of murine mast cell development and trafficking : tracking the roots and routes of the mast cell
- 2007
-
Ingår i: Immunological Reviews. - 0105-2896 .- 1600-065X. ; 217:1, s. 8-18
-
Forskningsöversikt (refereegranskat)abstract
- The appreciation of the role of the mast cell (MC) in inflammatory processes has expanded dramatically during the last decade. Many of these processes, especially more prolonged responses, are accompanied by an increase in the number of MCs, and much of this increase is likely because of recruitment of immature progenitors with subsequent maturation under the control of the tissue microenvironment. We have begun to identify many of the cell-surface molecules that control this influx and have traced the development of these cells back to their hematopoietic roots. This development proceeds along the myelomonocytic pathway with distinct intermediates having been identified in both bone marrow and spleen. The expression of alpha4beta7 integrins has played a prominent role in this process, as it helped identify a bipotent basophil MC precursor in the spleens of C57BL/6 mice. This integrin also controls basal influx into the intestine and, along with alpha4beta1 integrins, plays a critical role in recruitment to inflamed lungs. Investigation of chemokines and chemokine receptors in these processes led to the identification of a dual role for the murine interleukin-8 receptor CXCR2. This alpha-chemokine receptor affects MC progenitor trafficking by its expression by MC progenitors and by its expression on stromal cells, likely endothelium, affecting trafficking to both intestine under basal conditions and lung during inflammatory recruitment.
|
|
| 9. |
- Hallgren, Jenny, et al.
(författare)
-
Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors
- 2007
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:51, s. 20478-20483
-
Tidskriftsartikel (refereegranskat)abstract
- Chemokine receptors regulate the trafficking of leukocytes by mediating chemotaxis and by their influence on the expression and/or affinity of leukocyte integrins. Using blocking mAb, we showed that antigen-induced recruitment of mast cell progenitors (MCp) to the lung requires interaction of a4 integrins on the MCp with endothelial vascular cell adhesion molecule 1 (VCAM-1). In seeking a chemokine component, we found that CXCR2-deficient but not CCR3- or CCR5-deficient sensitized and antigen-challenged mice have significantly fewer lung MCp 1 day after challenge and fewer tracheal intraepithelial MC 1 week after challenge, implying that recruited MCp provide the source for these mature MC. Unexpectedly, reconstitution of sensitized, sublethally irradiated +/+ and -/- mice with bone marrow cells of either genotype indicated that expression of CXCR2 by the migrating MCp was not required. Instead, receptor function by resident lung cells was required because normal BM did not reconstitute MCp recruitment in irradiated CXCR2(-/-) mice. The reduced MCp influx into the lung of CXCR2(-/-) mice was accompanied by reduced induction of VCAM-1 transcripts and reduced endothelial surface expression. Thus, these studies demonstrate a role for a chemokine receptor in regulating endothelial VCAM-1 expression, MCp migration, and the level of intraepithelial MC in the lung of aerosolized, antigen-challenged mice.
|
|
| 10. |
- Jones, Tatiana G, et al.
(författare)
-
Antigen-induced increases in pulmonary mast cell progenitor numbers depend on IL-9 and CD1d-restricted NKT cells
- 2009
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 183:8, s. 5251-5260
-
Tidskriftsartikel (refereegranskat)abstract
- Pulmonary mast cell progenitor (MCp) numbers increase dramatically in sensitized and aerosolized Ag-challenged mice. This increase depends on CD4(+) T cells, as no MCp increase occurs in the lungs of sensitized wild-type (WT) mice after mAb depletion of CD4(+) but not CD8(+) cells before aerosol Ag challenge. Neither the genetic absence of IL-4, IL-4Ralpha chain, STAT-6, IFN-gamma, or IL-12p40 nor mAb blockade of IFN-gamma, IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17A, IL-12p40, or IL-12p40Rbeta1 before Ag challenge in WT mice reduces the pulmonary MCp increase. However, sensitized and Ag-challenged IL-9-deficient mice and sensitized WT mice given mAb to IL-9 just before Ag challenge show significant reductions in elicited lung MCp/10(6) mononuclear cells of 47 and 66%, respectively. CD1d-deficient mice and WT mice receiving anti-CD1d before Ag challenge also show significant reductions of 65 and 59%, respectively, in elicited lung MCp/10(6) mononuclear cells, revealing an additional requirement for MCp recruitment. However, in Jalpha18-deficient mice, which lack only type 1 or invariant NKT cells, the increase in the numbers of lung MCp with Ag challenge was intact, indicating that their recruitment must be mediated by type 2 NKT cells. Furthermore, anti-CD1d treatment of IL-9-deficient mice or anti-IL-9 treatment of CD1d-deficient mice does not further reduce the significant partial impairment of MCp recruitment occurring with a single deficiency. These findings implicate type 2 NKT cells and IL-9 as central regulators that function in the same pathway mediating the Ag-induced increase in numbers of pulmonary MCp.
|
|
| 11. |
- Succar, Julien, et al.
(författare)
-
Mouse Mast Cell Protease-4 Recruits Leukocytes in the Inflammatory Phase of Surgically Wounded Skin
- 2019
-
Ingår i: ADVANCES IN WOUND CARE. - : MARY ANN LIEBERT, INC. - 2162-1918 .- 2162-1934. ; 8:10, s. 469-475
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Mouse mast cell protease-4 (mMCP-4, also known as chymase) has both pro- and anti-inflammatory roles depending on the disease model. However, its effects have not been studied in surgically wounded skin. Given the significant clinical applications of modulating the inflammatory response in wound healing, we examined the role of mMCP-4 and the effect of its inhibitor chymostatin on leukocyte and polymorphonuclear cell (PMN) recruitment in our skin model. Approach: Recruitment was assessed on day-1 postwounding of three groups of mice (n = 10 each): mMCP-4 null mice, wild-type (WT) mice treated with the mMCP-4 inhibitor chymostatin, and WT with no other intervention. Leukocytes were stained with CD-45 cell marker, and PMN cells were stained with chloroacetate esterase. Results: The WT mice had 27 +/- 9 leukocytes per field compared with 11 +/- 6 for the mMCP-4 nulls, a decrease of 60% (p = 0.03), whereas the chymostatin-injected group had a count comparable with the uninjected WT controls at 24 +/- 9. The WT group had a PMN count of 96 +/- 12 cells, compared with just 24 +/- 8 in the mMCP-4 null group, a decrease of 75% (p = 0.001), whereas the chymostatin-treated group had 60 +/- 18 cells, a decrease of 38% compared with the WT group (p = 0.03). Innovation: We showed that the inflammatory process can be influenced by impeding the arrival of PMNs into the surgically injured site using the mMCP-4 inhibitor chymostatin. Conclusion: Chymase contributes to the recruitment of white blood cells in surgically wounded skin.
|
|
| 12. |
- Younan, George, et al.
(författare)
-
The inflammatory response after an epidermal burn depends on the activities of mouse mast cell proteases 4 and 5
- 2010
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 185:12, s. 7681-7690
-
Tidskriftsartikel (refereegranskat)abstract
- A second-degree epidermal scald burn in mice elicits an inflammatory response mediated by natural IgM directed to nonmuscle myosin with complement activation that results in ulceration and scarring. We find that such burn injury is associated with early mast cell (MC) degranulation and is absent in WBB6F1-Kit(W)/Kit(Wv) mice, which lack MCs in a context of other defects due to a mutation of the Kit receptor. To address further an MC role, we used transgenic strains with normal lineage development and a deficiency in a specific secretory granule component. Mouse strains lacking the MC-restricted chymase, mouse MC protease (mMCP)-4, or elastase, mMCP-5, show decreased injury after a second-degree scald burn, whereas mice lacking the MC-restricted tryptases, mMCP-6 and mMCP-7, or MC-specific carboxypeptidase A3 activity are not protected. Histologic sections showed some disruption of the epidermis at the scald site in the protected strains suggesting the possibility of topical reconstitution of full injury. Topical application of recombinant mMCP-5 or human neutrophil elastase to the scalded area increases epidermal injury with subsequent ulceration and scarring, both clinically and morphologically, in mMCP-5-deficient mice. Restoration of injury requires that topical administration of recombinant mMCP-5 occurs within the first hour postburn. Importantly, topical application of human MC chymase restores burn injury to scalded mMCP-4-deficient mice but not to mMCP-5-deficient mice revealing nonredundant actions for these two MC proteases in a model of innate inflammatory injury with remodeling.
|
|
