Reduction of GPSM3 expression akin to the arthritis-protective SNP rs204989 differentially affects migration in a neutrophil model.
G Protein Signaling Modulator-3 (GPSM3) is a leukocyte-specific regulator of G protein-coupled receptors (GPCRs), which binds inactivated Gαi·GDP subunits and precludes their reassociation with Gβγ subunits. GPSM3 deficiency protects mice from inflammatory arthritis and, in humans, GPSM3 single-nucleotide polymorphisms (SNPs) are inversely associated with the risk of rheumatoid arthritis development; recently, these polymorphisms were linked to one particular SNP (rs204989) that decreases GPSM3 transcript abundance. However, the precise role of GPSM3 in leukocyte biology is unknown. Here, we show that GPSM3 is induced in the human promyelocytic leukemia NB4 cell line following retinoic acid treatment, which differentiates this cell line into a model of neutrophil physiology (NB4*). Reducing GPSM3 expression in NB4* cells, akin to the effect ascribed to the rs204989 C>T transition, disrupts cellular migration toward leukotriene B4 (LTB4) and (to a lesser extent) interleukin-8 (a.k.a. IL-8 or CXCL8), but not migration toward formylated peptides (fMLP). As the chemoattractants LTB4 and CXCL8 are involved in recruitment of neutrophils to the arthritic joint, our results suggest that the arthritis-protective GPSM3 SNP rs204989 may act to decrease neutrophil chemoattractant responsiveness.
Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA.
B J
BJ
Gall
Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA.
A B
AB
Schroer
Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA.
J D
JD
Gross
Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA.|Department of Behavioral Medicine and Psychiatry, West Virginia University School of Medicine, Morgantown, WV, USA.
V
V
Setola
Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA.
D P
DP
Siderovski
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D019891:Leukopoiesis; D007975:Leukotriene B4 / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D014212:Tretinoin / Q000378:metabolism
C487218:GPSM3 protein, human; D020730:Guanine Nucleotide Dissociation Inhibitors; D016209:Interleukin-8; D007975:Leukotriene B4; D014212:Tretinoin; D009240:N-Formylmethionine Leucyl-Phenylalanine