Abstract
ObjectiveMolecular 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.ResultsComposite 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.InferenceT 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.ConclusionsAs 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.
Highlights
The production of superoxide anions (O2- ) by neutrophils and other phagocytes is an important step in our body's innate immune response. [1,2]
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 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
Absolute inflammatory migration profile measured by increase in cell number in tissues versus their sites of poiesis and circulation, i.e.bone marrow and peripheral blood respectively was increased (Table 2)
Summary
The production of superoxide anions (O2- ) by neutrophils and other phagocytes is an important step in our body's innate immune response. [1,2]. NADPH oxidase, the primary source of reactive oxygen species is a strong candidate for the development of therapeutic agents to ameliorate inflammation and end-organ damage [8,9]. It has been demonstrated that oxidants potently and efficiently inactivate matrilysin (MMP-7) by cross-linking adjacent tryptophan-glycine residues within the catalytic domain of the enzyme. These in vitro observations suggest that MMP inactivation can occur on or near phagocytes that produce both MMPs and reactive intermediates. Inherited deficiency of gp91phox, a phagocyte-specific component of the NADPH oxidase required for oxidant production, and targeted deletion of its mouse homologue result in granuloma formation and excessive tissue destruction [12]
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Schedule a callMore From: Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology
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