Eosinophil-mediated cholinergic nerve remodeling.
Eosinophils are observed to localize to cholinergic nerves in a variety of inflammatory conditions such as asthma, rhinitis, eosinophilic gastroenteritis, and inflammatory bowel disease, where they are also responsible for the induction of cell signaling. We hypothesized that a consequence of eosinophil localization to cholinergic nerves would involve a neural remodeling process. Eosinophil co-culture with cholinergic IMR32 cells led to increased expression of the M2 muscarinic receptor, with this induction being mediated via an adhesion-dependent release of eosinophil proteins, including major basic protein and nerve growth factor. Studies on the promoter sequence of the M2 receptor indicated that this induction was initiated at a transcription start site 145 kb upstream of the gene-coding region. This promoter site contains binding sites for a variety of transcription factors including SP1, AP1, and AP2. Eosinophils also induced the expression of several cholinergic genes involved in the synthesis, storage, and metabolism of acetylcholine, including the enzymes choline acetyltransferase, vesicular acetylcholine transferase, and acetylcholinesterase. The observed eosinophil-induced changes in enzyme content were associated with a reduction in intracellular neural acetylcholine but an increase in choline content, suggesting increased acetylcholine turnover and a reduction in acetylcholinesterase activity, in turn suggesting reduced catabolism of acetylcholine. Together these data suggest that eosinophil localization to cholinergic nerves induces neural remodeling, promoting a cholinergic phenotype.
Durcan
Niamh
N
Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
Costello
Richard W
RW
McLean
W Graham
WG
Blusztajn
Jan
J
Madziar
Beata
B
Fenech
Anthony G
AG
Hall
Ian P
IP
Gleich
Gerard J
GJ
McGarvey
Lorcan
L
Walsh
Marie-Therese
MT
D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D047091:Eosinophil Granule Proteins / Q000378:metabolism; D004804:Eosinophils / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D019899:Paracrine Communication; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D024363:Transcription Initiation Site; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics / Q000378:metabolism
D047091:Eosinophil Granule Proteins; D012333:RNA, Messenger; D043585:Receptor, Muscarinic M2; C493459:SLC18A3 protein, human; D050494:Vesicular Acetylcholine Transport Proteins; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D000109:Acetylcholine