S100A12 provokes mast cell activation: a potential amplification pathway in asthma and innate immunity.
BACKGROUND
The calcium-binding protein S100A12 might provoke inflammation and monocyte recruitment through the receptor for advanced glycation end products.


OBJECTIVE
Because inflammation elicited by S100A12 in vivo had characteristics of mast cell (MC) activation, we aimed to define the mechanism.


METHODS
Various MC populations were used to test S100A12 activation assessed on the basis of morphology, histamine release, leukotriene production, and cytokine induction. MC dependence of S100A12-provoked inflammation was tested in mice and on the rat microcirculation by means of intravital microscopy. Immunohistochemistry localized S100A12 in the asthmatic lung, and levels in sputum from asthmatic patients were quantitated by means of ELISA. Expression of the receptor for advanced glycation end products was evaluated by means of RT-PCR and Western blotting.


RESULTS
S100A12 provoked degranulation of mucosal and tissue MCs in vitro and in vivo and amplified IgE-mediated responses. It induced a cytokine profile indicating a role in innate/T(H)1-mediated responses. S100A12-induced edema and leukocyte rolling, adhesion, and transmigration in the microcirculation were MC dependent. Eosinophils in airway tissue from asthmatic patients were S100A12 positive, and levels were increased in sputum. S100A12 responses were partially blocked by an antagonist to the receptor for advanced glycation end products, but MCs did not express mRNA or protein, suggesting an alternate receptor.


CONCLUSIONS
This novel pathway highlights the potential importance of S100A12 in allergic responses and in infectious and chronic inflammatory diseases.


CONCLUSIONS
MC activation by S100A12 might exacerbate allergic inflammation and asthma. S100A12 might provide a novel marker for eosinophilic asthma.
Yang
Zheng
Z
School of Medical Sciences, The University of New South Wales, Sydney, Australia.
Yan
Wei Xing
WX
Cai
Hong
H
Tedla
Nicodemus
N
Armishaw
Chris
C
Di Girolamo
Nick
N
Wang
Hong Wei
HW
Hampartzoumian
Taline
T
Simpson
Jodie L
JL
Gibson
Peter G
PG
Hunt
John
J
Hart
Prue
P
Hughes
J Margaret
JM
Perry
Michael A
MA
Alewood
Paul F
PF
Geczy
Carolyn L
CL
D000328:Adult; D000818:Animals; D001249:Asthma / Q000276:immunology*; D001987:Bronchiectasis / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D009418:S100 Proteins / Q000494:pharmacology*; D000067616:S100A12 Protein; D013183:Sputum / Q000737:chemistry
D016207:Cytokines; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human