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Role of T cells in a gp91phox knockout murine model of acute allergic asthma.

Banerjee ER, Henderson WR - Allergy Asthma Clin Immunol (2013)

Bottom Line: Molecular regulation of inflammation, especially, the role of effector cells in NADPH oxidase-mediated redox reactions for producing O2- (superoxide anion) is a critical step.Materials and Methods and Treatment: To clarify the role of NADPH oxidase in the pathophysiology of T cell-initiatedmacrophage-associated allergic asthma, we induced allergen dependent inflammation in a gp91phox-/- SKO (single knockout) and a gp91phox-/- MMP-12-/- DKO (double knockout) mouse and analysed trafficking and functionality of various cell types, the T cell function and T cell-macrophage interaction being given special emphasis.Composite asthma symptoms expressed in a more aggravated manner in both the KO (SKO and DKO) mice compared to WT indicating that some redundancy may exist in the response pathways of gp91phox and MMP-12.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center for Allergy and Inflammation, University of Washington, Room 254, 850 Republican Street, Seattle, WA 98109, USA. enarb1@gmail.com.

ABSTRACT

Objective: Molecular regulation of inflammation, especially, the role of effector cells in NADPH oxidase-mediated redox reactions for producing O2- (superoxide anion) is a critical step. This study explores the roles of macrophages and neutrophils and their cross-talk with extra-cellular matrix components in the light of the role essayed by T cells. Materials and Methods and Treatment: To clarify the role of NADPH oxidase in the pathophysiology of T cell-initiatedmacrophage-associated allergic asthma, we induced allergen dependent inflammation in a gp91phox-/- SKO (single knockout) and a gp91phox-/- MMP-12-/- DKO (double knockout) mouse and analysed trafficking and functionality of various cell types, the T cell function and T cell-macrophage interaction being given special emphasis.

Results: Composite asthma symptoms expressed in a more aggravated manner in both the KO (SKO and DKO) mice compared to WT indicating that some redundancy may exist in the response pathways of gp91phox and MMP-12. On the one hand, upregulation in macrophage functions such as proliferation, mixed lymphocyte reaction, and MCP-1 directed chemotaxis, may indicate that a regulatory cross-talk is switched on between T cell and macrophage and on the other, downregulation of respiratory burst response hints at a dichotomy in their signaling pathways. Increased B7.1 but reduced B7.2 and MHC class II expression on KO alveolar macrophages may suggest that a switching on-off mechanism is operative where alteration of co-stimulatory molecule expression selectively activating T cell is a critical step.

Inference: T cell mediated functions such as Th2 cytokine secretion, and T cell proliferation in response to OVA were upregulated synchronous with the overall robustness of the asthma phenotype.

Conclusions: As far as cell-cell interaction is concerned, the data is indicative of the existence of a plethora of networks where molecular switches may exist that selectively induce activation and deactivation of regulatory pathways that ultimately manifest in the overall response. gp91phox and MMP-12 either redundantly or synergistically but not additively, provide a regulatory checkpoint for restricting T cell cross-talk with macrophages and keep excessive tissue damage and ECM degradation during acute allergic inflammation under control.

No MeSH data available.


Related in: MedlinePlus

Decreased iNOS + cells in KO mice. Cells from all tissues viz. BM, PB, Spleen, lung and BALf of NOX−/− vs. WT with and without OVA. or we could put % and # in tabular form. A1-E1. Percent iNOS positive cells in BM, PB, Spleen, LP and BALf respectively. A2-E2. Number of iNOS positive cells in BM, PB, Spleen, LP and BALf respectively cells in million. Data shows mean of 2 independent experiments which were pooled ± SEM. (* denotes p value<0.05 compared to WO). Abbreviations used are: WT=wildtype, NOX=gp91phox−/−, WA=WT+alum, WO=WT+OVA, NOXA=gp91phox−/−+alum, NOXO=gp91phox−/−+OVA.
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Figure 8: Decreased iNOS + cells in KO mice. Cells from all tissues viz. BM, PB, Spleen, lung and BALf of NOX−/− vs. WT with and without OVA. or we could put % and # in tabular form. A1-E1. Percent iNOS positive cells in BM, PB, Spleen, LP and BALf respectively. A2-E2. Number of iNOS positive cells in BM, PB, Spleen, LP and BALf respectively cells in million. Data shows mean of 2 independent experiments which were pooled ± SEM. (* denotes p value<0.05 compared to WO). Abbreviations used are: WT=wildtype, NOX=gp91phox−/−, WA=WT+alum, WO=WT+OVA, NOXA=gp91phox−/−+alum, NOXO=gp91phox−/−+OVA.

Mentions: iNOS is a surface enzyme expressed by macrophages that are of the M1 or killer phenotype. Figure 8 shows decrease in percent iNOS+ cells in PB, spleen, lung and BALf but not BM of KO mice in comparison to corresponding tissues from WT micemay indicate that there is a skewing of macrophage phenotype from killer to healer phenotype. This corroborates well with data in Figures 5 and 6 that these macrophages although migrating to the inflammatory focus in increased numbers are incapable of typical phagocytic functions which indicates a clear dichotomy in their signaling pathways.


Role of T cells in a gp91phox knockout murine model of acute allergic asthma.

Banerjee ER, Henderson WR - Allergy Asthma Clin Immunol (2013)

Decreased iNOS + cells in KO mice. Cells from all tissues viz. BM, PB, Spleen, lung and BALf of NOX−/− vs. WT with and without OVA. or we could put % and # in tabular form. A1-E1. Percent iNOS positive cells in BM, PB, Spleen, LP and BALf respectively. A2-E2. Number of iNOS positive cells in BM, PB, Spleen, LP and BALf respectively cells in million. Data shows mean of 2 independent experiments which were pooled ± SEM. (* denotes p value<0.05 compared to WO). Abbreviations used are: WT=wildtype, NOX=gp91phox−/−, WA=WT+alum, WO=WT+OVA, NOXA=gp91phox−/−+alum, NOXO=gp91phox−/−+OVA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643823&req=5

Figure 8: Decreased iNOS + cells in KO mice. Cells from all tissues viz. BM, PB, Spleen, lung and BALf of NOX−/− vs. WT with and without OVA. or we could put % and # in tabular form. A1-E1. Percent iNOS positive cells in BM, PB, Spleen, LP and BALf respectively. A2-E2. Number of iNOS positive cells in BM, PB, Spleen, LP and BALf respectively cells in million. Data shows mean of 2 independent experiments which were pooled ± SEM. (* denotes p value<0.05 compared to WO). Abbreviations used are: WT=wildtype, NOX=gp91phox−/−, WA=WT+alum, WO=WT+OVA, NOXA=gp91phox−/−+alum, NOXO=gp91phox−/−+OVA.
Mentions: iNOS is a surface enzyme expressed by macrophages that are of the M1 or killer phenotype. Figure 8 shows decrease in percent iNOS+ cells in PB, spleen, lung and BALf but not BM of KO mice in comparison to corresponding tissues from WT micemay indicate that there is a skewing of macrophage phenotype from killer to healer phenotype. This corroborates well with data in Figures 5 and 6 that these macrophages although migrating to the inflammatory focus in increased numbers are incapable of typical phagocytic functions which indicates a clear dichotomy in their signaling pathways.

Bottom Line: Molecular regulation of inflammation, especially, the role of effector cells in NADPH oxidase-mediated redox reactions for producing O2- (superoxide anion) is a critical step.Materials and Methods and Treatment: To clarify the role of NADPH oxidase in the pathophysiology of T cell-initiatedmacrophage-associated allergic asthma, we induced allergen dependent inflammation in a gp91phox-/- SKO (single knockout) and a gp91phox-/- MMP-12-/- DKO (double knockout) mouse and analysed trafficking and functionality of various cell types, the T cell function and T cell-macrophage interaction being given special emphasis.Composite asthma symptoms expressed in a more aggravated manner in both the KO (SKO and DKO) mice compared to WT indicating that some redundancy may exist in the response pathways of gp91phox and MMP-12.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center for Allergy and Inflammation, University of Washington, Room 254, 850 Republican Street, Seattle, WA 98109, USA. enarb1@gmail.com.

ABSTRACT

Objective: Molecular regulation of inflammation, especially, the role of effector cells in NADPH oxidase-mediated redox reactions for producing O2- (superoxide anion) is a critical step. This study explores the roles of macrophages and neutrophils and their cross-talk with extra-cellular matrix components in the light of the role essayed by T cells. Materials and Methods and Treatment: To clarify the role of NADPH oxidase in the pathophysiology of T cell-initiatedmacrophage-associated allergic asthma, we induced allergen dependent inflammation in a gp91phox-/- SKO (single knockout) and a gp91phox-/- MMP-12-/- DKO (double knockout) mouse and analysed trafficking and functionality of various cell types, the T cell function and T cell-macrophage interaction being given special emphasis.

Results: Composite asthma symptoms expressed in a more aggravated manner in both the KO (SKO and DKO) mice compared to WT indicating that some redundancy may exist in the response pathways of gp91phox and MMP-12. On the one hand, upregulation in macrophage functions such as proliferation, mixed lymphocyte reaction, and MCP-1 directed chemotaxis, may indicate that a regulatory cross-talk is switched on between T cell and macrophage and on the other, downregulation of respiratory burst response hints at a dichotomy in their signaling pathways. Increased B7.1 but reduced B7.2 and MHC class II expression on KO alveolar macrophages may suggest that a switching on-off mechanism is operative where alteration of co-stimulatory molecule expression selectively activating T cell is a critical step.

Inference: T cell mediated functions such as Th2 cytokine secretion, and T cell proliferation in response to OVA were upregulated synchronous with the overall robustness of the asthma phenotype.

Conclusions: As far as cell-cell interaction is concerned, the data is indicative of the existence of a plethora of networks where molecular switches may exist that selectively induce activation and deactivation of regulatory pathways that ultimately manifest in the overall response. gp91phox and MMP-12 either redundantly or synergistically but not additively, provide a regulatory checkpoint for restricting T cell cross-talk with macrophages and keep excessive tissue damage and ECM degradation during acute allergic inflammation under control.

No MeSH data available.


Related in: MedlinePlus