Universität zu Köln

Isfort, Katrin, Ebert, Franziska, Bornhorst, Julia, Sargin, Sarah, Kardakaris, Rozina, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Baehler, Martin, Schwerdtle, Tanja, Schwab, Albrecht and Hanley, Peter J. (2011). Real-time Imaging Reveals That P2Y(2) and P2Y(12) Receptor Agonists Are Not Chemoattractants and Macrophage Chemotaxis to Complement C5a Is Phosphatidylinositol 3-Kinase (PI3K)- and p38 Mitogen-activated Protein Kinase (MAPK)-independent. J. Biol. Chem., 286 (52). S. 44776 - 44788. ROCKVILLE: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. ISSN 1083-351X

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Abstract

Adenosine 5'-triphosphate (ATP) has been implicated in the recruitment of professional phagocytes (neutrophils and macrophages) to sites of infection and tissue injury in two distinct ways. First, ATP itself is thought to be a chemotactic find me signal released by dying cells, and second, autocrine ATP signaling is implicated as an amplifier mechanism for chemotactic navigation to end-target chemoattractants, such as complement C5a. Here we show using real-time chemotaxis assays that mouse peritoneal macrophages do not directionally migrate to stable analogs of ATP (adenosine-5'-(gamma-thio)-triphosphate (ATP gamma S)) or its hydrolysis product ADP (adenosine-5'-(gamma-thio)-diphosphate (ADP beta S)). HPLC revealed that these synthetic P2Y(2) (ATP gamma S) and P2Y(12) (ADP gamma S) receptor ligands were in fact slowly degraded. We also found that ATP gamma S, but not ADP beta S, promoted chemokinesis (increased random migration). Furthermore, we found that photorelease of ATP or ADP induced lamellipodial membrane extensions. At the cell signaling level, C5a, but not ATP gamma S, activated Akt, whereas both ligands induced p38 MAPK activation. p38 MAPK and Akt activation are strongly implicated in neutrophil chemotaxis. However, we found that inhibitors of phosphatidylinositol 3-kinase (PI3K; upstream of Akt) and p38 MAPK(or conditional deletion of p38 alpha MAPK) did not impair macrophage chemotactic efficiency or migration velocity. Our results suggest that PI3K and p38 MAPK are redundant for macrophage chemotaxis and that purinergic P2Y(2) and P2Y(12) receptor ligands are not chemotactic. We propose that ATP signaling is strictly autocrine or paracrine and that ATP and ADP may act as short-range touch me (rather than long-range find me) signals to promote phagocytic clearance via cell spreading.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Isfort, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Ebert, Franziska UNSPECIFIED UNSPECIFIED UNSPECIFIED Bornhorst, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Sargin, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Kardakaris, Rozina UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Baehler, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwerdtle, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwab, Albrecht UNSPECIFIED UNSPECIFIED UNSPECIFIED Hanley, Peter J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-483225
DOI:	10.1074/jbc.M111.289793
Journal or Publication Title:	J. Biol. Chem.
Volume:	286
Number:	52
Page Range:	S. 44776 - 44788
Date:	2011
Publisher:	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Place of Publication:	ROCKVILLE
ISSN:	1083-351X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EXTRACELLULAR ATP; NEUTROPHIL CHEMOTAXIS; INDUCE CHEMOTAXIS; IN-VIVO; CELLS; SIGNAL; ADP; NUCLEOTIDES; BRAIN; MICE Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48322