How to activate mast cells: Receptors and ligands Master Table (part 1)

There are many receptors on mast cells.  The molecules that bind to these receptors are called ligands.  Different receptors can cause activation in different ways.

I am posting this table a little at a time as I anticipate getting a lot of questions about it.  I put this together for my own reference and I didn’t keep track of all sources.  I am hoping to go through the literature again and track this at some point.

These tables are not exhaustive, and I’ll add to them over time as I have the chance.

Receptor Ligand (molecules that bind to the receptor) Result
0X40 0X40 ligand Suppression of mast cell activation
A2A, A2B, A3 Adenosine At low concentration, degranulation:

histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

De novo: IL-1b, IL-3, IL-4, IL-8, IL-13

 

At high concentration, inhibits FcεRI degranulation

C3α receptor C3α De novo:
IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 

Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

Increases IgE and IgG dependent degranulation

C5α receptor C5α Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

Cannabinoid CB2 receptor 2-arachidonoyl-glycerol, anandamide Suppression of mast cell activity
CCR1 CCL3 (MIP1α), CCL5 (RANTES) Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
CCR3 CCL11 No degranulation
Increases IgE dependent secretion: IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5
CCR4 CCL2 (MCP-1) No degranulation, reléase of cytokines
CCR5 CCL3 (MIP1α), CCL5 (RANTES), CCL4 (MIP1β) No degranulation, reléase of cytokines
CD200 receptor CD200 (OX2) Inhibitory
Cd300α receptor Eosinophilic granule proteins Inhibitory
CD47 (integrin associated protein, IAP) Integrins Histamine secretion
CD48 E. coli, M. tuberculosis Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

De novo : TNFa, IL-6

CD72 CD100 Inhibits CKIT activation
CKIT receptor tyrosine kinase (CD117) Stem cell factor De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 

Increased IgE dependent degranulation: histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

Corticotropin/ corticotropin releasing hormone receptor CRH, urocortin Secretion of VEGF
CX3CL1 Fractalkine No degranulation
CX3CR1 Chemokines No degranulation, reléase of cytokines
Estrogen receptor Estrogens Increased IgE dependent degranulation: histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
ETA Endothelin-1 Degranulation: Histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin, renin

 

De novo: TNFa, IL-6, VEGF, TGF-b1

ETB Endothelin-1 Unknown
FcαR (CD89) IgA Unknown
FcγRIIA, FcγRI, FcγRIIIA IgG/antigen Degranulation: Histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin, renin

 

De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

FcγRIIIB IgG/antigen Cannot induce activation
FcεRI IgE with or without antigen Degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

 

De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

How to activate mast cells: Complement protein C3a

The complement system is part of the innate immune system. It is composed of many small proteins that circulate as inactive precursor molecules. When the immune system is triggered, enzymes cleave these precursors to form activate cytokines. These cytokines then cleave other precursors to form even more cytokines. This is known as a cascade and it amplifies the inflammatory signal to draw other inflammatory cells and molecules.

Mast cells express many receptors on their surfaces. The one people are most familiar with is the IgE receptor, also called FceRI. One of the receptors mast cells express is for C3a, a fragment of complement protein C3. This fragment is produced by the complement activation cascade. C3a is known for inducing smooth muscle contraction, increasing vascular permeability, recruiting white blood cells to the site of skin injection, and attracting macrophages, neutrophils, some lymphocytes, basophils and mast cells.

Something I haven’t touched on much is the fact that there are two major categories of mast cells in the body. Mucosal mast cells live in the GI mucosa. Serosal mast cells live in the skin, peritoneum and respiratory tract. These two populations have different mediators in their granules and respond differently to stimuli like C3a. In mucosal mast cells, C3a actually inhibits histamine and TNF release. In serosal mast cells, C3a increases degranulation of cells stimulated by IgE or IgG.

C3a has also been shown to cause expression of particular genes in mast cells that participate in production of cytokines. This is achieved by multiple pathways, one that works at low concentrations of C3a (cell surface GPCR) and one that works at higher concentrations (activation of G proteins).

In patients with allergic asthma, inhaled allergens like dust, dust mites, Aspergillus and ragweed pollen, activate the complement system in the mucosa of the respiratory tract. This generates the formation of C3a. Cells around mast cells release enzymes that can cleave C3 to form C3a. When mast cells become activated, they release a number of enzymes that may also cleave C3 to form C3a. Tryptase has been shown to do this in vitro, meaning in a reaction outside of the body.

When some receptors are stimulated too often, they become desensitized. This causes a signal to be sent into the cell that makes the cell internalize the receptor, or literally remove it from the surface so it can’t be activated anymore. This is the case for mast cell C3a receptors. I am curious to know if C3a receptors in mast cell patients don’t get desensitized. In theory, this would result in huge, fast allergic reactions without IgE stimulation and chronic activation of the inflammatory response. This has not been investigated to my knowledge.

Several mast cell mediators, including histamine, make blood vessels more permeable. Some researchers hypothesize that this action works to draw C3 to the activated mast cells. C3 can then be cleaved by tryptase, producing C3a, and amplifying the allergic reaction. Due to its well characterized role in anaphylaxis and allergic response, C3a is known as an anaphylatoxin.

 

References:

Erdei et al. Regulation of mast cell activation by complement-derived peptides. Immunology Letters 92 (2004) 39–42.

Ali H. Regulation of human mast cell and basophil function by anaphylatoxins C3a and C5a. Immunology Letters 128 (2010) 36–45.

M.R. Woolhiser, K. Brockow, D.D. Metcalfe. Activation of human mast cells by aggregated IgG through FcγRI: additive effects of C3a, Clin. Immunol. 110 (2004) 172–180.

T.C. Theoharides et al. Mast cells and inflammation. Biochimica et Biophysica Acta 1822 (2012) 21–33.