Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance

TY - JOUR

T1 - Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance

AU - Houthuijzen, Julia M

AU - Oosterom, Ilse

AU - Hudson, Brian D

AU - Hirasawa, Akira

AU - Daenen, Laura G M

AU - McLean, Chelsea M

AU - Hansen, Steffen V F

AU - van Jaarsveld, Marijn T M

AU - Peeper, Daniel S

AU - Jafari Sadatmand, Sahar

AU - Roodhart, Jeanine M L

AU - van de Lest, Chris H A

AU - Ulven, Trond

AU - Ishihara, Kenji

AU - Milligan, Graeme

AU - Voest, Emile

N1 - © The Author(s).

PY - 2017/5

Y1 - 2017/5

N2 - Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts its effect by activating splenic F4/80+/CD11blow macrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80+/CD11blow macrophages as the relevant receptor for 16:4(n-3). Studies that used splenocytes from GPR120-deficientmice have confirmed this conclusion. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA2 activity in these splenic macrophages and secretion of the resistance-inducing lipidmediator, lysophosphatidylcholine(24:1). These studies identify anovel and unexpected function for GPR120 and suggest that antagonists of this receptormightbe effective agents to limit development of chemotherapy resistance.

AB - Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts its effect by activating splenic F4/80+/CD11blow macrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80+/CD11blow macrophages as the relevant receptor for 16:4(n-3). Studies that used splenocytes from GPR120-deficientmice have confirmed this conclusion. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA2 activity in these splenic macrophages and secretion of the resistance-inducing lipidmediator, lysophosphatidylcholine(24:1). These studies identify anovel and unexpected function for GPR120 and suggest that antagonists of this receptormightbe effective agents to limit development of chemotherapy resistance.

KW - Journal Article

U2 - 10.1096/fj.201601248r

DO - 10.1096/fj.201601248r

M3 - Journal article

C2 - 28183801

SN - 0892-6638

VL - 31

SP - 2195

EP - 2209

JO - F A S E B Journal

JF - F A S E B Journal

IS - 5

ER -