Novel role of the CXC chemokine receptor 3 in inflammatory response to arterial injury: involvement of mTORC1.
Atherosclerosis, restenosis, and posttransplant graft atherosclerosis are characterized by endothelial damage, infiltration of inflammatory cells, and proliferation of smooth muscle cells. The CXCR3-activating chemokines interferon-gamma inducible protein 10 (IP10) and MIG (monokine induced by interferon-gamma) have been implicated in vascular repair and remodeling. The underlying molecular mechanisms, however, remain elusive. Here, we show that wire-mediated arterial injury induced local and systemic expression of IP10 and MIG, resulting in enhanced recruitment of CXCR3(+) leukocytes and hematopoietic progenitor cells. This was accompanied by profound activation of mammalian target of rapamycin complex (mTORC)1, increased reactive oxygen species production, apoptosis, and intimal hyperplasia. Genetic and pharmacological inactivation of CXCR3 signaling not only suppressed recruitment of inflammatory cells but also abolished mTORC1 activation, reduced reactive oxygen species generation, and blocked apoptosis of vascular cells, resulting in significant reduction of intimal hyperplasia in vivo. In vitro, stimulation of T cells with IP10 directly activated mTORC1 and induced generation of reactive oxygen species and apoptosis in an mTORC1-dependent manner. These results strongly indicate that CXCR3-dependent activation of mTORC1 directly links stimulation of the Th1 immune system with the proliferative response of intimal cells in vascular remodeling.
Schwarz
Johannes B K
JB
Deutsches Herzzentrum, 1. Medizinische Klinik, Technische Universität München, München, Germany.
Langwieser
Nicolas
N
Langwieser
Nicole N
NN
Bek
Martin J
MJ
Seidl
Stefan
S
Eckstein
Hans-Henning
HH
Lu
Bao
B
Schömig
Albert
A
Pavenstädt
Hermann
H
Zohlnhöfer
Dietlind
D
D000818:Animals; D017209:Apoptosis; D002317:Cardiovascular Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D002633:Chemotaxis; D004195:Disease Models, Animal; D000068338:Everolimus; D005263:Femoral Artery / Q000187:drug effects / Q000276:immunology* / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D006965:Hyperplasia; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D002317:Cardiovascular Agents; D002352:Carrier Proteins; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D017382:Reactive Oxygen Species; D054367:Receptors, CXCR3; D000068338:Everolimus; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus