Mechanisms of tolldependent regulation of allergic asthma

TLR-mediated activation of the innate immune system can either diminish or exacerbate asthma, depending on the dose, timing, duration of the exposure to the TLR ligand, and the genetic background of the affected individual. TLR agonists can act as adjuvants during sensitization. Epidemiologic and murine data support the theory that chronic exposure to TLR agonists early in life protects against the future development of asthma. Activation of the innate immune system with acute exposures to TLR agonists can adversely affect airways disease in patients with existing lung disease by either promoting the recruitment of inflammatory cells into the lung or enhancing the proinflammatory response to inhaled allergen. Therefore, TLR-dependent signaling can modify allergic inflammation by at least four independent mechanisms depending on dose, duration of exposure and host factors. These four independent mechanisms of regulation of allergic inflammation include; as an adjuvant during sensitization to antigen, enhanced allergic inflammation with acute exposures at moderate dose, enhanced neutrophilic inflammation at high dose and suppression of allergic response with chronic low dose exposure. As shown in Figure 1, the role of toll-like receptors in airways disease appears to be a two-edged sword. Low dose exposure to TLR ligands early in life potentially protects against future development of asthma, while exposure later in life can contribute to the progression of asthma. Clear understanding of the TLR-dependent mechanisms, which regulate allergic inflammation, will be required to introduce novel therapeutic interventions.

As TLR signaling can either exacerbate or attenuate airway disease, it is likely that TLRs affect multiple cellular and molecular mechanisms that affect the asthma phenotype in different ways. The protective effect of endotoxin on asthma has been

Figure 1

Context and dose of endotoxin impact the development of allergic inflammation Furthermore, the biologic impact of endotoxin dose is determined by genetic background (normal solid, CD14 (-159T or-1619G) dotted, TLR4 (D299G) dashed). In normal individuals; low dose endotoxin can act as an adjuvant during sensitization, chronic exposure can attenuate allergic inflammation, acute exposure to moderate doses of LPS can enhance allergic inflammation, acute high dose exposures can cause neutrophilic inflammation (solid line). CD14 polymorphisms, associated with enhanced response to endotoxin, results in enhanced suppression with chronic low dose, enhanced allergic inflammation with moderate dose LPS, and enhanced neutrophilic inflammation with high dose LPS (dotted line). Conversely, TLR4 polymorphisms, associated with blunted response to endotoxin, results in reduced suppression with chronic low dose LPS, reduced response to moderate dose LPS, and reduced response to high dose LPS (dashed line).

Figure 1

Context and dose of endotoxin impact the development of allergic inflammation Furthermore, the biologic impact of endotoxin dose is determined by genetic background (normal solid, CD14 (-159T or-1619G) dotted, TLR4 (D299G) dashed). In normal individuals; low dose endotoxin can act as an adjuvant during sensitization, chronic exposure can attenuate allergic inflammation, acute exposure to moderate doses of LPS can enhance allergic inflammation, acute high dose exposures can cause neutrophilic inflammation (solid line). CD14 polymorphisms, associated with enhanced response to endotoxin, results in enhanced suppression with chronic low dose, enhanced allergic inflammation with moderate dose LPS, and enhanced neutrophilic inflammation with high dose LPS (dotted line). Conversely, TLR4 polymorphisms, associated with blunted response to endotoxin, results in reduced suppression with chronic low dose LPS, reduced response to moderate dose LPS, and reduced response to high dose LPS (dashed line).

widely ascribed to the stimulation by TLR signaling on TH1 responses, which can, in some settings down-regulate TH2 responses [127]. For example, the TH1 cytokine IL-12 increases levels of IFN-y and IL-18 and causes a reduction in allergen-induced airways hyper-responsiveness [128]. However, several other lines of evidence call into question the notion that the ratio of TH1 and TH2 cytokines is directly linked to asthma. For example, transfer of antigen-specific TH1 cells fail to diminish allergic inflammation in allergen-challenged mice [129, 130] and helminth-infected children, in some developing countries, have very high levels of TH2 cytokines but have a very low incidence of allergies [131-133]. While TLR-ligands are associated with the production of TH1 cytokines, it has become evident that TH1 cells can either downregulate or augment the asthma phenotype [130, 134, 135]. Interestingly, in an antigen specific model of allergic inflammation, recruitment of TH2 cells is preceded by infiltration of TH1 cells, suggesting a role of TH1 cells in allergic inflammation [130]. Adoptive transfer experiments support the cooperative role of both Th1 and TH2 cells to promote eosinophilic airway inflammation [135]. Similar cooperativity is observed in respiratory viral infections where TH1-prominent inflammation leads to enhanced TH2 allergic inflammation [136]. These observations support the possibility that low to moderate doses of inhaled TLR ligands could promote early recruitment of TH1 cells into the lung, which in turn, enhance both TH2 cell recruitment into the lung and the asthma phenotype. TLR specific regulation of TH1 and TH2 cell recruitment into the lungs and the impact on subsequent asthma phenotype has not yet been reported. Therefore, it remains unclear whether TLR-dependent alteration in the TH1/TH2 balance directly contributes to the incidence or severity of allergic asthma and it is likely that other TLR-dependent mechanisms play an important role.

The effect of TLR ligands on asthma might be related to their impact on dendritic cells (DCs), the potent antigen presenting cells residing in the parenchyma of the lung and many other organs. TLR signaling in DCs results in increased levels of co-stimulatory molecules and proinflammatory cytokines [137], which facilitate adaptive immune responses to the antigen. Although most studies of this type have shown that TLR signaling leads to production of TH1 cytokines and stimulate this type of immune response, some evidence suggests that TLR4 can also contribute to Th2 immune responses. Thus, C3H/HeJ mice demonstrate reduced levels of allergic responses to ovalbumin than control mice [138]. In addition, low doses of aerosolized endotoxin together with ovalbumin can sensitize mice to this antigen, whereas ovalbumin on its own cannot [78]. The latter finding in particular suggests that although DCs have not been shown to produce TH2 cytokines upon stimulation with TLR ligands, their capacity to promote TH2 responses might nonetheless be enhanced. In contrast to these observations, however, bone marrow-derived DCs treated with both antigen and moderate doses of endotoxin suppress TH2 airway response [139]. However, levels of endotoxin vary widely among different commercially-available preparations of ovalbumin, and results from different investigators are therefore difficult to interpret, even when apparently similar procedures are used. In addition to their apparent ability to act as an adjuvant during sensitization, TLR ligands can also enhance allergic inflammation when provided during the chal lenge phase of the response. This property might also be related to TLR signaling in DCs because these cells are necessary to maintain immune responses in the lung, even in previously sensitized mice [140]. Endotoxin-dependent recruitment of TH2 cells into the lung can occur independently of a specific allergen challenge [82] and might also be related to TLR signaling in DCs.

Another mechanistic possibility to explain the actions of TLR ligands involves their impact on THl-independent regulation of allergic responses. T regulatory cells (Treg) have emerged in recent years as important negative modulators of immune responses [141]. These cells, which often display both CD4 and CD25 on their surface, regulate the actions of other T cells by both cell-cell interactions and production of inhibitory cytokines such as IL-10 or TGF-P [142-144]. The impact of TLR ligands on Treg cells is only beginning to be understood, but it appears that these lig-ands can both enhance and inhibit Treg function. Thus, IL-6, a cytokine produced by DCs upon stimulation by either endotoxin or CpG, can block the suppressive activity of CD4+/CD25+ Treg cells [145]. On the other hand, these Treg cells express many types of TLRs and proliferate in response to stimulation with endotoxin [146]. Furthermore, direct stimulation of CD4+/CD25+ Treg cells with endotoxin enhances their suppressor activity [146] and TLR3-dependent induction of IL-10 in CD4+/CD25+ T cells has been linked to suppression of immunity against Candida albicans [147]. These observations suggest that TLR signaling can either enhance or inhibit Treg cells activity. Although the relationship between dose and duration of exposure to TLR ligands and Treg activity has not been carefully studied, it is reasonable to suggest that these levels might differentially impact Treg cell function.

Finally, the ability of unmethylated CpG DNA to attenuate allergic inflammation suggests that these molecules may have therapeutic utility. CpG DNA elicits a TH1-mediated immune response, which might explain its ability to reverse the TH2-medi-ated allergic phenotype. The cells responsible for this activity might be either DCs [148] or B cells, both of which express TLR9 [149]. While the molecular mechanism related to CpG DNA suppression of allergic responses remain unclear, recent work by Hayashi et al. reveal that unmethylated CpG DNA induce high levels of indoleamine 2.3-dioxygenase (IDO) [150], which can inhibit T cell reactivity [151] and also induce Treg response [152]. Increased levels of IDO are associated with attenuation of eosinophilic inflammation and airway hyper-reactivity in a murine model of asthma [150]. Thus, induction of IDO might be a mechanism by which unmethylated CpG attenuates allergic phenotypes in models of asthma.

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