Abr, a Negative Regulator of Rac, Attenuates Cockroach Allergen–Induced Asthma in a Mouse Model

Abstract

Abr deactivates Rac, a master molecular switch that positively regulates many immune cell functions, by converting it to its GDP-bound conformation. Here we report that in the absence of Abr function, cockroach allergen (CRA)-immunized mice experienced a fatal asthma attack when challenged with CRA. The asthma in abr−/− mice was characterized by increased pulmonary mucus production, elevated serum IgE and leukocyte airway infiltration. Decreased pulmonary compliance was further documented by increased airway resistance upon methacholine challenge. Peribronchial and bronchio-alveolar lavage eosinophils, key cells associated with allergic asthma, were increased in abr−/− mice, but adoptive transfer of this cell type from immunized mice to naïve controls followed by CRA challenge showed that eosinophils are not primarily responsible for differences in airway resistance between controls and abr null mutants. CD4+ T cell numbers in the airways of CRA-challenged abr−/− mice were also significantly increased compared to controls, as were the Th2 T cell-secreted cytokines IL-4 and IL-5 in total lung. Interestingly, when control and abr−/− CD4+ T cells from CRA-immunized mice were transferred to wild type animals, airway resistance upon challenge with CRA was significantly higher in mice transplanted with T cells lacking Abr function. CD4+ T cells from CRA-immunized and challenged abr−/− mice contained elevated levels of activated Rac-GTP, compared to wild type controls. Functionally, abr−/− CD4+ T cells from CRA-exposed mice showed significantly enhanced chemotaxis towards CCL21. These results identify Abr-regulated CD4+ T cell migration as an important component of severe cockroach allergen evoked allergic asthma in mice.

Cellular mechanisms underlying steroid-resistant asthma

“…Mice were systemically sensitised with ovalbumin (Ova) and aluminium hydroxide intraperitoneally, followed 10-12 days later by inhaled Ova challenge to induce AAD. Other mouse models of allergic asthma widely use other allergens, such as house dust mite [57][58][59], Alternaria [60] or cockroach [61] antigen. Our mice were left for 20 days and were re-challenged on days 33-34 of the model, in order to model an allergen-induced exacerbation of disease.…”

Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness

“…However, our result is in agreement with a protective role of Rac inhibitors already described in pulmonary inflammation and asthma. 13,34 In summary, our results in mice and human tissues reveal a new and fundamental role of Rac1 to promote aSMC contraction and AHR. Rac1 inhibition simultaneously prevents both AHR and pulmonary inflammation, offering the opportunity to aggregate in a single molecule the desired anti-inflammatory and bronchodilatory actions of antiasthma therapy.…”

“…30 Interestingly, inhalation of Rac inhibitors not only prevented AHR by inhibiting SMC Rac1 but also decreased pulmonary inflammation, probably by blocking Rac activity in immune/inflammatory cells. In fact, activation of Rac in leukocytes has been described to be involved in respiratory inflammation, 13,15,31 and it is well established that allergic asthma-associated airway inflammation is involved in AHR. 15,32 Rac has also been reported to control epithelial barrier function and although specific deletion of Rac1 in the epithelial cells did not affect the integrity of the airway epithelium in vivo in basal condition, it exacerbated inflammation and augmented T H 2 cytokines in asthma models induced by house dust mite extract or OVA as allergens.…”

“…9 As intracellular signaling molecules activated by extracellular stimuli, small GTPases of the Rho family (RhoA, Rac1, and Cdc42) act as molecular switches that regulate signaling cascades controlling SMC functions. 10 Increasing evidence implicates the Rho protein Rac1 in the regulation of vascular SMC contraction, 11,12 and genetic deletion of Rac1 regulator 13 or effector 14 has been shown to modulate AHR in experimental allergic models. Furthermore, Rac1 has been identified last year as a potential link between pulmonary inflammation and bronchoconstriction.…”

Cistrome-based Cooperation between Airway Epithelial Glucocorticoid Receptor and NF-κB Orchestrates Anti-inflammatory Effects

“…7A), the gene that encodes for ␣1 antitrypsin, a major genetic cause of emphysema in humans (62); EDN2, whose disruption causes emphysema in mice (63); SOD2, which protects the airway epithelium from oxidative damage (64,65); SERPINA3, which encodes the ␣1 anti-chymotrypsin gene, a potent inhibitor of mast cell proteases that is implicated in asthma pathogenesis (66,67); FOXP4, which represses goblet cell differentiation and mucus secretion (68); and ABR (Fig. 7A), a RAC inhibitor whose deficiency worsens airway hyperresponsiveness and inflammation in murine allergic asthma models (69). Cooperative regulation of TNFAIP3 and IRAK3 was also reconfirmed, and several genes with less well described biologic functions, such as FSTL3 (Fig.…”