mediator

I posted earlier this week about Toll-like receptors (TLRs). These are receptors on the outside of mast cells (and other cells) that tell them there is an infection. Instead of only being able to bind very specific molecules like receptors often do, these TLRs are able to bind lots of molecules that look alike. Once these are bound, it tells mast cells to activate, make mediators and release them.

After TLR2, TLR4 is the most well understood Toll-like receptor. Molecules that bind TLR4 are from infectious gram negative bacteria, several viruses (including RSV), Cryptococcus neoformans, and Candida albicans. It also binds fibrinogen, which is involved in the clotting cascade, and nickel. When infected with a gram negative bacteria, like E. coli or Ps. aeruginosa, mast cells secrete inflammatory molecules TNF, IL-6, IL-13, and IL-1b.

TLR4 also has a very intriguing behavior with opioid receptors on mast cells. These opioid receptors are the binding sites for opiate medications, like morphine, which are common triggers for mast cell patients. One study found that treatment with morphine actually interferes with TLR4 making inflammatory molecules. Other studies have found that opiates can bind TLR-4 directly. When bound, TLR-4 signals for release of TNFa, CCL1 and IL-5.

Other TLRs on mast cells can be bound by various molecules and produce and release mediators in return. TLR3 is bound by viral proteins and induces release of interferon a and b; TLR5 binds proteins from some flagellated bacteria and releases TNF and IL-1b; TLR9 binds unmethylated DNA of the type released by bacteria and DNA viruses, and releases interferon a, TNF, IL-1b and leukotrienes.

All TLR receptors can function independently of IgE. This is one example of an IgE independent pathway, or a way mast cells can degranulate or secrete mediators without IgE.

 

References:

Hilary Sandig and Silvia Bulfone-Paus. TLR signaling in mast cells: common and unique features. Front Immunol. 2012; 3: 185.

Abraham S. N, St John A. L. (2010). Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 10440–452.

Dietrich N., Rohde M., Geffers R., Kroger A., Hauser H., Weiss S., Gekara N. O. (2010). Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria. Proc. Natl. Acad. Sci. U.S.A.1078748–8753

Gilfillan A. M., Tkaczyk C. (2006). Integrated signalling pathways for mast-cell activation. Nat. Rev. Immunol.6218–230.

Fehrenbach K., Port F., Grochowy G., Kalis C., Bessler W., Galanos C., Krystal G., Freudenberg M., Huber M. (2007). Stimulation of mast cells via FcvarepsilonR1 and TLR2: the type of ligand determines the outcome. Mol. Immunol. 442087–2094.

McCurdy,J.D., Olynych,T.J., Maher, L. H.,and Marshall, J.S.(2003). Cutting edge: distinct Toll-like receptor2 activators selectively induce different classes of mediator production from human mast cells. J. Immunol. 170, 1625–1629.

Medina-Tamayo, J., Ibarra-Sanchez, A., Padilla-Trejo,A., and Gonzalez- Espinosa, C. (2011). IgE-dependent sensitization increases responsiveness to LPS but does not modify development of endotoxin tolerance in mast cells. Inflamm. Res. 60, 19–27.

Qiao,H., Andrade,M.V., Lisboa,F. A., Morgan,K., and Beaven, M. A. (2006).FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107, 610–618.

Yoshioka,M., Fukuishi,N., Iriguchi,S., Ohsaki, K., Yamanobe,H., Inukai, A., Kurihara,D., Imajo,N., Yasui, Y., Matsui, N., Tsujita, T., Ishii, A., Seya,T., Takahama,M., and Akagi, M. (2007). Lipoteichoicacid down- regulates FcepsilonRI expressionon human mast cells through Toll-like receptor2. J. Allergy Clin. Immunol. 120, 452–461.

Varadaradjalou, S., Feger, F., Thieblemont, N., Hamouda, N.B., Pleau, J. M., Dy,M., and Arock, M. (2003). Toll-likereceptor2 (TLR2)and TLR4 differentially activate human mast cells. Eur. J. Immunol. 33, 899–906.