Lipoprotein I, a TLR2/4 Ligand Modulates Th2-Driven Allergic Immune Responses

Abstract

Asthma is an inflammatory lung disease that is initiated and directed by Th2 and inhibited by Th1 cytokines. Microbial infections have been shown to prevent allergic responses by inducing the secretion of the Th1 cytokines IL-12 and IFN-γ. In this study, we examined whether administration of lipoprotein I (OprI) from Pseudomonas aeruginosa could prevent the inflammatory and physiological manifestations of asthma in a murine model of OVA-induced allergic asthma. OprI triggered dendritic cells to make IL-12 and TNF-α, with subsequent IFN-γ production from T cells. OprI stimulation of dendritic cells involved both TLR2 and TLR4. Intranasal coadministration of OprI with OVA allergen resulted in a significant decrease in airway eosinophilia and Th2 (IL-4 and IL-13) cytokines and this effect was sustained after repeated allergen challenge. The immediate suppressive effect of OprI (within 2 days of administration) was accompanied by an increase in Th1 cytokine IFN-γ production and a significant, but transient infiltration of neutrophils. OprI did not redirect the immune system toward a Th1 response since no increased activation of locally recruited Th1 cells could be observed upon repeated challenge with allergen. Our data show for the first time that a bacterial lipoprotein can modulate allergen-specific Th2 effector cells in an allergic response in vivo for a prolonged period via stimulation of the TLR2/4 signaling pathway.

A synthetic toll-like receptor 2 ligand decreases allergic immune responses in a mouse rhinitis model sensitized to mite allergen

“…Previous studies have evaluated the effect of TLR2 signaling on allergic diseases, but the results are conflicting. In our model, triggering of TLR2 with Pam3CSK4 showed a beneficial antiallergic effect on allergic rhinitis, which is consistent with several pre- vious studies (Akdis et al, 2003;Patel et al, 2005;Revets et al, 2005). The mechanism of its antiallergic effect is still elusive.…”

“…Studies in TLR4 signaling showed that stimulation of TLR4 by relatively high dose of lipopolysaccharide reduced allergic inflam-mation in a murine model of asthma (Rodriguez et al, 2003). However, the role of TLR2 signaling in allergy remains controversial, since several studies reported that TLR2 ligands administered to murine models of allergy during the sensitization period led to an enhancement of Th2-mediated allergic inflammation (Chisholm et al, 2004;Redecke et al, 2004), while others showed TLR2 activation with its ligands suppressed Th2-type responses and IgE production in animal models either before or after airway allergen challenge (Patel et al, 2005;Revets et al, 2005). TLR2 recognizes components from a variety of microorganisms including lipoproteins, peptidoglycan and lipoteichoic acid mainly from Gram-negative bacteria.…”

Regulatory T cells: which role in the pathogenesis and treatment of allergic disorders?

“…However, the concern is that whole pathogens might also induce the production of proinflammatory cytokines through TLR ligation, the extent of which will determine whether downregulation of allergic responses or pathology ensues. Indeed, probiotic not only induce IL-10 production, but they also increase the production of IFN-c (80) or they induce the production of IFN-c alone (52,53), thus again supporting the concept that their preventive activity on the development of allergic reactions is mediated by a combined mechanism of immune suppression and immune deviation or perhaps by immune deviation alone. An exception to the rule that bacteria or their components do induce immune deviation rather than immune suppression seems to be Mycobacterium vaccae, whose administration during allergen sensitization or challenge suppressed asthmatic features by mediating allergen-specific Treg cells to produce both IL-10 and TGF-b (81).…”

CARMA1 Is Critical for the Development of Allergic Airway Inflammation in a Murine Model of Asthma

“…with 10 g of chicken egg albumin (OVA) (SigmaAldrich) bound to 1 mg of aluminum hydroxide (Type V; Sigma-Aldrich) suspended in 0.5 cc of PBS (Mediatech) on days 0 and 7. This preparation of OVA has been shown to have Ͻ1 U of endotoxin per milligram of OVA (25). Mice underwent aerosol challenge with nebulized OVA (10 mg/ml in PBS) or with PBS alone on days 14 -16.…”