G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte function and its deficiency protects from inflammatory arthritis
| Autor: | M.W. McGinnis, Oded Foreman, Brian K. Buckley, Patrick M. Giguère, Teresa K. Tarrant, Peng Liu, Denise Esserman, Roman G. Timoshchenko, David P. Siderovski, Matthew J. Billard, Geneviève Laroche |
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| Rok vydání: | 2012 |
| Předmět: |
CCR2
Chemokine Cell Survival Inflammatory arthritis Immunology Arthritis Biology CCL2 Monocytes Article Autoimmune Diseases Chemokine receptor Mice medicine Animals Myeloid Cells CX3CL1 Molecular Biology Guanine Nucleotide Dissociation Inhibitors Mice Knockout Monocyte medicine.disease Arthritis Experimental Disease Models Animal medicine.anatomical_structure biology.protein Cytokines Receptors Chemokine Inflammation Mediators |
| Zdroj: | Molecular immunology. 54(2) |
| ISSN: | 1872-9142 |
| Popis: | Polymorphism at the GPSM3 gene locus is inversely associated with four systemic autoimmune diseases, including rheumatoid arthritis and ankylosing spondylitis. G-protein signaling modulator-3 (GPSM3) expression is most pronounced in myeloid cells, in which it targets heterotrimeric G-protein Gαi subunits of chemokine receptors, critical to immune function. To begin to explore the regulatory role of GPSM3 in monocytes, human THP-1 and primary mouse myeloid cells were cultured under stimulus conditions; GPSM3 was found by immunoblotting to be expressed at highest levels in the mature monocyte. To evaluate the effects of GPSM3 deficiency on a myeloid-dependent autoimmune disease, collagen antibody-induced arthritis (CAIA) was induced in Gpsm3 −/− and control mice, which were then analyzed for clinical score, paw swelling, intra-articular proinflammatory markers, and histopathology. Mice lacking GPSM3 were protected from CAIA, and expression of monocyte-representative pro-inflammatory chemokine receptors and cytokines in paws of Gpsm3 −/− mice were decreased. Flow cytometry, apoptosis, and transwell chemotaxis experiments were conducted to further characterize the effect of GPSM3 deficiency on survival and chemokine responsiveness of monocytes. GPSM3-deficient myeloid cells had reduced migration ex vivo to CCL2, CX3CL1, and chemerin and enhanced apoptosis in vitro . Our results suggest that GPSM3 is an important regulator of monocyte function involving mechanisms of differentiation, survival, and chemotaxis, and deficiency in GPSM3 expression is protective in acute inflammatory arthritis. |
| Databáze: | OpenAIRE |
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