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Modulation of asthma and allergy by addressing toll-like receptor 2
Journal of Occupational Medicine and Toxicology volume 3, Article number: S5 (2008)
Toll-like receptors play an important role in innate and adaptive immunity and in balancing immune responses with tolerance. TLR2 is related to protection against allergies and allergic asthma by sensing pathogen associated patterns as lipoproteins and lipopeptides. A constant Th1 triggering is thought to prevent Th2 related disorders.
TLR2 is expressed on a variety of cells, both structural as well as immune cells. Importantly, TLR2 is also expressed on dendritic cells, which are thought to be one of the key players of initiating and maintaining immune responses. Therefore, TLR2 on dendritic cells is a good target for modulating immunity either to Th1 or Th2 responses, or induction of tolerance.
TLR2 agonists show high immunomodulatory and adjuvantic capacity. This makes TLR2 agonisation a promising approach for pharmaceutical intervention of allergic disorders.
Since a human homologue to drosophila toll-receptor had been firstly described , the family of TLR increased in members. Furthermore, knowledge broadens about TLR, their role in innate and adaptive immunity and their implication in balancing immune responses with tolerance. One possible mechanism herein is suppression of CD4+CD25+ regulatory T cells, allowing the host to develop an adequate adaptive immune response against microbacteria .
Formulation of the hygiene hypothesis pointed out an inverse association of microbial load and Th2 disorders [3, 4]. Additionally, genetic variations in TLR2, but not in TLR4 , seem to sign responsible for an observed protection of farmers' children from allergy and asthma . These protective actions seem to be of special importance to start already during pregnancy, when prenatal exposure to farm stables upregulates TLR expression of neonatal cells .
On the other hand, smoking during pregnancy attenuates TLR-mediated immune responses, possibly increasing the risk for the offspring to develop allergies and asthma .
TLR2 is expressed on a variety of cells, both structural as well as immune cells, in humans and rodents as there are neutrophils , small airway epithelial cells as well as airway smooth muscle cells [10, 11], tracheal muscle layer , monocytes , macrophages , glial cells , murine bone-marrow derived mast cells , and B cells [17, 18]. Its expression is inducible by TNF-α and IFN-γ.
Very importantly, TLR2 is also expressed on DCs, which are thought to be one of the key players of initiating and maintaining immune responses, and therefore are a good target cell for modulating immunity either to Th1 or Th2 responses, or induction of tolerance [19–21].
TLR2 in general senses lipopeptides and lipoproteins, whereby different heterodimers recognise different structures: diacylated lipopeptides, e.g. MALP-2 , require TLR2/6 [9, 23], whereas triacylated lipopeptides, e.g. Pam3CysSK4, are recognised by TLR2/1  and lipoproteins by TLR2/4 .
Nevertheless, animal models remain a useful tool to investigate preventive or therapeutic effects related to TLR2.
Effects of TLR2 agonisation
Administration of MALP-2 into the airways attracts neutrophils to the bronchoalveolar space within 24 h. Two to three days after instillation, macrophages become more prominent. On macrophages, TLR2 agonists show clear activating effects . After 72 h, lymphocytes, although less in number, reach their maximum contribution to cellularity of BALF. These effects revealed after 10 d . Furthermore, changes in lung histology occur after MALP-2 aerosol administration, where the area of bronchus-associated lymphoid tissue is increased. The functional relevance of this finding remains to be investigated [28, 29].
Immunostimulation in allergy and allergic asthma
TLR2 agonisation bears the potency to both inhibit and promote development of immune responses and is therefore manifold in its implementation.
Mycoplasma infections prevent asthma, an effect which is partly dependent on the TLR2-IFN-γ -pathway . This finding lead to the development of small Mycoplasma-derived compounds for potential pharmacological intervention of allergic diseases. A modulation of an already existing allergy could be achieved by using such Mycoplasma-derived compounds, as for example MALP-2. Intratracheal treatment with this TLR2/6 agonist in combination with the Th1-cytokine IFN-γ clearly reduced AHR, eosinophilia and Th2 cytokines in BALF; however, neutrophils and IL-12p70 were induced . Likewise, treatment with a synthetic TLR2/1 ligand reduced total cell as well as eosinophil counts in the BALF, IL-4 and IL-5 levels as well as AHR. These reductions were independent from IL-10 and TGF-β , implicating rather a shift to a Th1 reaction than an induction of tolerance to be responsible for these observations. Additionally, TLR2/4 agonisation during allergen challenge in sensitised mice prevented allergic asthma. On DCs, IL-12 and TNF-α were induced, which by itself induces IFN-γ production of T lymphocytes. As a result, eosinophils, IL-4 and IL-13 were reduced, while neutrophil counts and IFN-γ were elevated, and no increased activation of Th1-lymphocytes could be detected . However, also the contrary effect could be observed: TLR2/1 agonisation aggravated allergic asthma when administered during the initial phase of the immune reaction. The type of TLR stimulation during this early phase seems to be a determinant for the polarisation of the adaptive immune response . When TLR2 ligands were administered during the efferent phase in a murine model of allergic conjunctivitis, the infiltration of eosinophils was suppressed, but rather by inducing a CD4+ cells apoptosis than by inducing a Th1 response . Investigations in an in vitro model of allergy demonstrated an induction of TNF-α and IL-10 synthesis, but not IL-12, when blood derived DCs were stimulated with MALP-2 . All these examples demonstrate the various implementations of TLR2 agonisation, either for shifting Th2 towards Th1, aggravating Th2 or induction of tolerance.
Its high immunomodulatory capacity as an adjuvant is further emphasised in experimental vaccination against HIV and measles [36–39]. This makes TLR2 agonisation a promising approach for pharmaceutical intervention.
TLR2 expression and function is influenced by administration of steroids, e.g. dexamethasone. On human airway smooth muscle cells, upregulation by cytokines as IFN-γ and TNF-α is potentiated; however, dexamethasone alone suppresses receptor expression . This might be an explanation of infectious exacerbations occurring in steroid treated asthma, in contrast to viral exacerbations mediated via TLR3 .
TLR2 is an important receptor in innate and adaptive immunity and related to protection against allergic disorders in humans. Due to their high immunomodulatory and adjuvantic capacity, TLR2 agonists bear manifold implications. Therefore, TLR2 agonists may provide potent new strategies either for prevention or treatment of allergies and allergic asthma.
Medzhitov R, Preston-Hurlburt P, Janeway CA: A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997,388(6640):394–7. 10.1038/41131
Pasare C, Medzhitov R: Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003,299(5609):1033–6. 10.1126/science.1078231
Yazdanbakhsh M, Kremsner PG, van Ree R: Allergy, parasites, and the hygiene hypothesis. Science 2002,296(5567):490–4. 10.1126/science.296.5567.490
Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grize L, Maisch S, Carr D, Gerlach F, Bufe A, Lauener RP, Schierl R, Renz H, Nowak D, von Mutius E: Environmental exposure to endotoxin and its relation to asthma in schoolage children. N Engl J Med 2002,347(12):869–77. Allergy and Endotoxin Study Team 10.1056/NEJMoa020057
Raby BA, Klimecki WT, Laprise C, Renaud Y, Faith J, Lemire M, Greenwood C, Weiland KM, Lange C, Palmer LJ, Lazarus R, Vercelli D, Kwiatkowski DJ, Silverman EK, Martinez FD, Hudson TJ, Weiss ST: Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes. Am J Respir Crit Care Med 2002,166(11):1449–56. 10.1164/rccm.200207-634OC
Eder W, Klimecki W, Yu L, von Mutius E, Riedler J, Braun-Fahrlander C, Nowak D, F D Martinez A: Toll like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 2004,113(3):482–8. 10.1016/j.jaci.2003.12.374
Ege MJ, Bieli C, Frei R, van Strien RT, Riedler J, Ublagger E, Schram Bijkerk D, Brunekreef B, van Hage M, Scheynius A, Pershagen G, Benz MR, Lauener R, von Mutius E, Braun-Fahrlander C: Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J Allergy Clin Immunol 2006,117(4):817–23. Parsifal Study team: 10.1016/j.jaci.2005.12.1307
Noakes PS, Hale J, Thomas R, Lane C, Devadason SG, Prescott SL: Maternal smoking is associated with impaired neonatal toll-like-receptor mediated immune responses. Eur Respir J 2006,28(4):675–7. 10.1183/09031936.06.00050206
Wilde I, Lotz S, Engelmann D, Starke A, van Zandberg G, Solbach W, Laskay T: Direct stimulatory effects of the TLR2/6 ligand bacterial lipopeptide MALP-2 on neutrophil granulocytes. Med Microbiol Immunol 2007,196(2):61–71. 10.1007/s00430-006-0027-9
Sukkar MB, Xie S, Khorasani NM, Kon OM, Stanbridge R, Issa R, Chung KF: Toll-like receptor 2, 3, and 4 expression and function in human airway smooth muscle. J Allergy Clin Immunol 2006,118(3):641–8. 10.1016/j.jaci.2006.05.013
Ritter M, Mennerich D, Weith A, Seither P: Characterization of Toll-like receptors in primary lung epithelial cells: strong impact of the TLR3 ligand poly(I:C) on the regulation of Toll-like receptors, adaptor proteins and inflammatory response. J Inflamm (Lond) 2005,2(1):16. 10.1186/1476-9255-2-16
Bachar O, Adner M, Uddmann R, Cardell LO: Toll like receptor stimulation induces airway hyperresponsiveness to bradykinin, an effect mediated by JNK and NF-κ-B signaling pathways. Eur J Immunol 2004,34(4):1196–207. 10.1002/eji.200324569
Harter L, Mica L, Stocker R, Trentz O, Keel M: Increased expression of toll-like receptor-2 and -4 on leukocytes from patients with sepsis. Shock 2004,22(5):403–9. 10.1097/01.shk.0000142256.23382.5d
Luhrmann A, Grote S, Stephan M, Tschernig T, Pabst R: Local pulmonary immune stimulation by the Toll-like receptor 2 and 6 ligand MALP-2 in rats is age dependent. Immunol Lett 2007,108(2):167–73. 10.1016/j.imlet.2006.12.008
Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK, Choi SY, Park K, Kim JS, Akira S, Na HS, Oh SB, Lee SJ: A critical role of toll-like receptor 2 in nerve injury induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem 2007,282(20):14975–83. 10.1074/jbc.M607277200
Fehrenbach K, Port F, Grochowy G, Kalis C, Bessler W, Galanos C, Krystal G, Freudenberg M, Huber M: Stimulation of mast cells via FCεR1 and TLR2: the type of ligand determines the outcome. Mol Immunol 2007,44(8):2087–94. 10.1016/j.molimm.2006.09.011
Borsutzky S, Kretschmer K, Becker PD, Muhlradt PF, Kirschning CJ, Weiss S, Guzman CA: The mucosal adjuvant macrophage-activating lipopeptide-2 directly stimulates B lymphocytes via the TLR2 without the need of accessory cells. J Immunol 2005,174(10):6308–13.
Pasare C, Medzhitov R: Control of B-cell responses by Toll-like receptors. Nature 2005,438(7066):364–8. 10.1038/nature04267
Duez C, Gosset P, Tonnel AB: Dendritic calls and toll like receptors in allergy and asthma. Eur J Dermatol 2006,16(1):12–6.
Link C, Gavioli R, Ebensen T, Canella A, Reinhard E, Guzman CA: The Toll-like receptor ligand MALP- 2 stimulates dendritic cell maturation and modulates proteasome composition and activity. Eur J Immunol 2004,34(3):899–907. 10.1002/eji.200324511
Blander JM, Medzhitov R: Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 2006,440(7085):808–12. 10.1038/nature04596
Takeuchi O, Kawai T, Muhlradt P, Morr M, Radolf JD, Zychlinsky A, Takeda K, Akira S: Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 2001,13(7):933–40. 10.1093/intimm/13.7.933
Into T, Dohkan JI, Inomata M, Nakashima M, Shibata KI, Matsushita K: Synthesis and characterization of a dipalmitoylated lipopeptide derived from paralogous lipoproteins of Mycoplasma pneumoniae. Infect Immun 2007,75(5):2253–9. 10.1128/IAI.00141-07
Revets H, Pynaert G, Grooten J, De Baetselier P: Lipoprotein I, a TLR2/4 ligand modulates Th2- driven allergic immune responses. J Immunol 2005,174(2):1097–103.
van Duin D, Mohanty S, Thomas V, Ginter S, Montgomery RR, Fikrig E, Allore HG, Medzhitov R, Shaw AC: Age-associated defect in human TLR-1/2 function. J Immunol 2007,178(2):970–5.
Muhlradt PF, Kiess M, Meyer H, Sussmuth R, Jung G: Isolation, structure elucidation and synthesis of macrophage stimulatory lipopeptide from Mycoplasma fermentans acting at picomolar concentrations. J Exp Med 1997, 185: 1951–1958. 10.1084/jem.185.11.1951
Luhrmann A, Deiters U, Skokowa J, Hanke M, Gessner JE, Muhlradt PF, Pabst R, Tschernig T: In vivo effects of a synthetic 2-kilodalton macrophage activating lipopeptide of Mycoplasma fermentans after pulmonary application. Infect Immun 2002,70(7):3785–3792. 10.1128/IAI.70.7.3785-3792.2002
Luhrmann A, Tschernig T, Pabst R: Stimulation of bronchus-associated lymphoid tissue in rats by repeated inhalation of aerosolized lipopeptide MALP-2. Pathobiology 2002,70(5):266–9. 10.1159/000070740
Charavaryamath C, Janardhan KS, Townsend HG, Willson P, Singh B: Multiple exposures to swine barn air induce lung inflammation and airway hyperresponsiveness. Respir Res 2005, 6: 50. 10.1186/1465-9921-6-50
Wu Q, Martin RJ, Rino JG, Jeyaseelan S, Breed R, Chu HW: A deficient TLR2 signaling promotes airway mucin production in Mycoplasma pneumoniae infected allergic mice. Am J Physiol Lung. Am J Physiol Lung Cell Mol Physiol 2007,292(5):L1064-L1072. 10.1152/ajplung.00301.2006
Weigt H, Nassenstein C, Tschernig T, Muhlradt PF, Krug N, Braun A: Efficacy of macrophage-activating lipopeptide-2 combined with interferon gamma in a murine asthma model. Am J Respir Crit Care Med 2005,172(5):566–72. 10.1164/rccm.200411-1490OC
Patel M, Xu D, Kewin P, Choo-Kang B, McSharry C, Thomson NC, Liew F: TLR2 agonist ameliorates allergic airway inflammation by promoting Th1 response and not via regualtory T cells. J Immunol 2005,174(12):7558–63.
Redecke V, Hacker H, Datta SK, Fermin A, Pitha PM, Broide DH, Raz E: Cutting edge: activation of Toll like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol 2004,172(5):2739–43.
Fukushima A, Yamaguchi T, Ishida W, Fukata K, Ueno H: TLR2 agonist ameliorates murine experimental allergic conjunctivitis by inducing CD4 positive T-cell apoptosis rather than affecting the Th1/Th2 balance. Biochem Biophys Res Commun 2006,339(4):1048–55. 10.1016/j.bbrc.2005.11.114
Weigt H, Muhlradt PF, Emmendorffer A, Krug N, Braun A: Synthetic mycoplasma-derived lipopeptide MALP-2 induces maturation and function of dendritic cells. Immunobiology 2003,207(3):223–33. 10.1078/0171-2985-00234
Becker PD, Fiorentini S, Link C, Tosti G, Ebensen T, Caruso A, Guzman CA: The HIV-1 matrix protein p17 can be efficiently delivered by intranasal route in mice using the TLR2/6 agonist MALP-2 as mucosal adjuvant. Vaccine 2006,24(25):5269–76. 10.1016/j.vaccine.2005.11.008
Luhrmann A, Tschernig T, Pabst R, Niewiesk S: Improved intranasal immunization with live attenuated measles virus after coinoculation of the lipopeptide MALP-2. Vaccine 2005,23(39):4721–6. 10.1016/j.vaccine.2005.05.009
Borsutzky S, Fiorelli V, Ebensen T, Tripiciano A, Rharbaoui F, Scoglio A, Link C, Nappi F, Morr M, Butto S, Cafaro A, Muhlradt PF, Ensoli B, Guzman CA: Efficient mucosal delivery of the HIV-1 Tat protein using the synthetic lipopeptide MALP-2 as an adjuvant. Eur J Immunol 2003,33(6):1548–56. 10.1002/eji.200323954
Rharbaoui F, Drabner B, Borsutzky S, Winckler U, Morr M, Ensoli B, Muhlradt PF, Guzman CA: The Mycoplasma-derived lipopeptide MALP-2 is a potent mucosal adjuvant. Eur J Immunol 2002,32(10):2857–65. 10.1002/1521-4141(2002010)32:10<2857::AID-IMMU2857>3.0.CO;2-R
The authors thank Cord Arnold, Laser Zentrum Hannover, for important contribution in drafting of the manuscript.
BF is funded by a stipend of the German Research Council (DFG).
This article has been published as part of Journal of Occupational Medicine and Toxicology Volume 3 Supplement 1, 2008: Proceedings of the 6th Workshop on Animal Models of Asthma. The full contents of the supplement are available online at http://www.occup-med.com/content/3/S1.
The authors declare that they have no competing interests.
BF drafted the manuscript. AB discussed and corrected the manuscript.
All authors read and approved the final manuscript.
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Fuchs, B., Braun, A. Modulation of asthma and allergy by addressing toll-like receptor 2. J Occup Med Toxicol 3, S5 (2008). https://doi.org/10.1186/1745-6673-3-S1-S5
- Allergic Asthma
- TLR2 Agonisation
- Airway Smooth Muscle Cell
- Allergic Disorder