Anti-inflammatory effects of an inflammatory chemokine: CCL2 inhibits lymphocyte homing by modulation of CCL21-triggered integrin-mediated adhesions.
Our studies focus on the pathways that restrict homing of specific subsets of immune cells, and thereby fine-tune the immune response at specific lymphoid and peripheral tissues. Here, we report that CCL2 (at picomolar [pM] levels) renders both murine and human T cells defective in their ability to develop CCR7-triggered activation of LFA-1- and LFA-1-mediated adhesion strengthening to endothelial ICAM-1 both in vitro and in vivo. CCL2 also attenuated lymphocyte chemotaxis toward lymph node chemokines. Consequently, low-dose CCL2 inhibited lymphocyte homing to peripheral lymph nodes but did not affect lymphocyte trafficking through the spleen. Impaired homing of lymphocytes to peripheral lymph nodes resulted in attenuated progression of both asthma and adjuvant arthritis. Thus, pM levels of circulating CCL2 can exert global suppressive effects on T-cell trafficking and differentiation within peripheral lymph nodes, and may be clinically beneficial as an anti-inflammatory agent.
Flaishon
Liat
L
Department of Immunology, the Weizmann Institute of Science, Rehovot, Israel.
Hart
Gili
G
Zelman
Einat
E
Moussion
Christine
C
Grabovsky
Valentin
V
Lapidot Tal
Guy
G
Feigelson
Sara
S
Margalit
Raanan
R
Harmelin
Alon
A
Avin-Wittenberg
Tamar
T
Shoseyov
David
D
Alon
Ronen
R
Girard
Jean-Philippe
JP
Shachar
Idit
I
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001168:Arthritis / Q000517:prevention & control; D001249:Asthma / Q000517:prevention & control; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000494:pharmacology*; D054421:Chemokine CCL21 / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D007109:Immunity; D016023:Integrins / Q000378:metabolism*; D008198:Lymph Nodes; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D054400:Receptors, CCR7 / Q000378:metabolism; D013154:Spleen
D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D054421:Chemokine CCL21; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D054400:Receptors, CCR7