Autologously up-regulated Fc receptor expression and action in airway smooth muscle mediates its altered responsiveness in the atopic asthmatic sensitized state

Abstract

To elucidate the role of IgE-dependent mechanisms in inducing altered airway responsiveness in the atopic asthmatic state, the expression and actions of Fc receptor activation were examined in isolated rabbit tracheal smooth muscle (TSM) tissue and cultured cells passively sensitized with sera from atopic asthmatic patients or nonatopic͞ nonasthmatic (control) subjects. Relative to control tissues, the atopic asthmatic-sensitized TSM exhibited significantly increased maximal isometric contractility to acetylcholine (P < 0.01) and attenuated maximal relaxation responses and sensitivity (i.e., ؊log ED 50 ) to isoproterenol (P < 0.005). These changes in agonist responsiveness in atopic sensitized TSM were ablated by pretreating the tissues with a blocking mAb to the low affinity receptor for IgE, FcRII (i.e., CD23) or by depleting the sensitizing serum of its immune complexes. Moreover, in complimentary experiments, exogenous administration of IgE immune complexes to naive TSM produced changes in agonist responsiveness that were qualitatively similar to those obtained in the atopic asthmatic-sensitized state. Extended studies further demonstrated that, in contrast to their respective controls, atopic asthmatic serum-sensitized human and rabbit TSM tissue and cultured cells exhibited markedly induced mRNA and cell surface expression of FcRII, whereas constitutive expression of the IgG receptor subtype, Fc␥RIII, was unaltered. Finally, the up-regulated mRNA expression of FcRII observed following exposure of TSM to atopic asthmatic serum or to exogenously administered IgE immune complexes was significantly inhibited by pretreating the tissues or cells with anti-CD23 mAb. Collectively, these observations provide evidence demonstrating that the altered agonist responsiveness in atopic asthmatic sensitized airway smooth muscle is largely attributed to IgEmediated induction of the autologous expression and activation of FcRII receptors in the airway smooth muscle itself.Bronchial asthma is characterized by airways inflammation, exaggerated airway reactivity to bronchoconstrictor agonists, and attenuated ␤-adrenoreceptor-mediated airway relaxation (1-3). In individuals with atopic asthma, mast cell activation has been implicated in mediating the immediate bronchoconstrictor response acutely following antigen inhalation, a process involving IgE-mediated activation of the high affinity IgE receptor (FcRI), leading to cellular degranulation and the release of various mast cell-derived mediators (4-6). The identification of Fc receptors on other cell types in the lung (e.g., mononuclear cells, eosinophils, and dendritic cells) suggests that, apart from mast cells per se, these other cell types may also serve to propagate the pro-inflammatory allergic pulmonary response, most likely via the orchestrated extended release of various cytokines (7-13). Accordingly, immune complex͞Fc receptor interactions potentially underlie the progression of the airway inflammatory and bronchoconstrictor responses in asthma, wherein the i...

The high-affinity IgE receptor (FcεRI): a critical regulator of airway smooth muscle cells?

“…The factors that influenced Fc⑀RI and Fc⑀RII expression and the contribution of each Fc⑀R in ASM cell function within the airways, e.g., airway hyperresponsiveness and inflammation, have not been investigated. Finally, it is not clear whether Fc⑀RI and Fc⑀RII/CD23 signaling events in ASM cells are similar to those in immune cells, i.e., mast cells and B cells, respectively, and whether a regulatory cross talk exists between Fc␥ (Fc␥RI, -RI, and RIII) (44) and Fc⑀R, the latter and GPCR receptors in ASM cells.…”

“…Furthermore, Fc⑀RII/ CD23 expression was upregulated on treatment with atopic asthmatic serum, containing high levels of IgE or exogenously administered IgE immune complexes (42,44). Activation of Fc⑀RII/CD23 by IgE immune complexes or atopic asthmatic serum provoked "proasthmatic-like" changes in ASM responsiveness, i.e., increased contractility or attenuated relaxation, which could be inhibited by a monoclonal anti-CD23 neutralizing antibody (42,44). More recently, Fc⑀RII/CD23 expression in human ASM cells was shown to be induced by IL-4, granulocyte/macrophage colony-stimulating factor (GM-CSF), or in combination (6).…”

“…Recently, the same group trying to investigate the mechanism underlying the induction of changes in ASM responsiveness in the atopic-sensitized state showed that both human and rabbit ASM tissues were able to constitutively express Fc⑀RII/ CD23 and Fc receptors for IgG, Fc␥RI (CD64), Fc␥RII (CD32), and Fc␥RIII (CD16) (42,44). Furthermore, Fc⑀RII/ CD23 expression was upregulated on treatment with atopic asthmatic serum, containing high levels of IgE or exogenously administered IgE immune complexes (42,44).…”

Airway Smooth Muscle in Asthma Symptoms: Culprit but Maybe Innocent

“…Most of these studies assessed ASM contractility by measuring its force-generating capacity. However, some studies also reported that some of these inflammatory insults change the velocity and amount of shortening of the ASM in response to a spasmogen (161), as well as its ability to relax in response to bronchodilators (8,15,78,81,89,216). The half-time of relaxation after short EFS-induced tetani has also been shown to increase (double) in ASM strips derived from dogs sensitized to ragweed (109).…”

“…At the molecular level, several asthma triggers have been shown to increase ASM contractility ex vivo. For example, ASM contractility has been shown to be enhanced following prolong (at least 16 h) incubation with atopic serum (15,19,78,89,91,161,211,245,246), IgE immune complex (80,89,250) and exogenous asthma triggers such as the house dust mite allergen Der p 1 (82), the bacterial endotoxin lipopolysaccharide (LPS) (8,166,216,220) and the rhinovirus (serotype 16) (78,81) or the virus mimetic toll-like receptor (TLR)3 ligand polyinosinic polycytidylic acid (poly-IC) (8). Most of these studies assessed ASM contractility by measuring its force-generating capacity.…”