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FPR2/ALX receptor expression and internalization are critical for lipoxin A 4 and annexin‐derived peptide‐stimulated phagocytosis
Open accessAbstract
Lipoxins (LXs) are endogenously produced eicosanoids with well‐described anti‐inflammatory and proresolution activities, stimulating nonphlogistic phagocytosis of apoptotic cells by macrophages. LXA 4 and the glucocorticoid‐derived annexin A1 peptide (Ac2–26) bind to a common G‐proteincoupled receptor, termed FPR2/ALX. However, direct evidence of the involvement of FPR2/ALX in the anti‐inflammatory and proresolution activity of LXA 4 is still to be investigated. Here we describe FPR2/ALX trafficking in response to LXA 4 and Ac2–26 stimulation. We have transfected cells with HA‐tagged FPR2/ALX and studied receptor trafficking in unstimulated, LXA 4 (1–10 nM)‐ and Ac2–26 (30 µM)‐treated cells using multiple approaches that include immunofluorescent confocal microscopy, immunogold labeling of cryosections, and ELISA and investigated receptor trafficking in agonist‐stimulated phagocytosis. We conclude that PKC‐dependent internalization of FPR2/ALX is required for phagocytosis. Using bone marrow‐derived macrophages (BMDMs) from mice in which the FPR2/ALX ortholog Fpr2 had been deleted, we observed the nonredundant function for this receptor in LXA 4 and Ac2–26 stimulated phagocytosis of apoptotic neutrophils. LXA 4 stimulated phagocytosis 1.7‐fold above basal ( P< 0.001) by BMDMs from wild‐type mice, whereas no effect was found on BMDMs from Fpr2 ‐/‐ mice. Similarly, Ac2–26 stimulates phagocytosis by BMDMs from wild‐type mice 1.5‐fold above basal ( P< 0.05). However, Ac2–26 failed to stimulate phagocytosis by BMDMs isolated from Fpr2 ‐/‐ mice relative to vehicle. These data reveal novel and complex mechanisms of the FPR2/ALX receptor trafficking and functionality in the resolution of inflammation.—Maderna, P., Cottell, D. C., Toivonen, T., Dufton, N., Dalli, J., Perretti, M., Godson, C. FPR2/ALX receptor expression and internalization are critical for lipoxin A 4 and annexinderived peptide‐stimulated phagocytosis. FASEB J . 24, 4240–4249 (2010). www.fasebj.org
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Cites
Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators
Serhan, C. N., Chiang, N., & Van Dyke, T. E. (2008) · Nature Reviews Immunology · doi:10.1038/nri2294 · Cited by 2,932
Resolution of inflammation: the beginning programs the end
Serhan, C. N., & Savill, J. (2005) · Nature Immunology · doi:10.1038/ni1276 · Cited by 2,552
Annexin A1 and glucocorticoids as effectors of the resolution of inflammation
Perretti, M., & D'Acquisto, F. (2009) · Nature Reviews Immunology · doi:10.1038/nri2470 · Cited by 915
Self-citationMaresins: Novel macrophage mediators with potent antiinflammatory and proresolving actions
Serhan, C. N., Yang, R., Martinod, K., Kasuga, K., Pillai, P. S., Porter, T. F., Oh, S. F., & Spite, M. (2009) · Journal of Experimental Medicine · doi:10.1084/jem.20081880 · Cited by 908
Mitchell, S., Thomas, G., Harvey, K., Cottell, D., Reville, K., Berlasconi, G., Petasis, N. A., Erwig, L., Rees, A. J., Savill, J., et al. (2002) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000032417.73640.72 · Cited by 287
Self-citationAnti-inflammatory circuitry: Lipoxin, aspirin-triggered lipoxins and their receptor ALX
Chiang, N., Arita, M., & Serhan, C. N. (2005) · Prostaglandins, Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2005.05.003 · Cited by 239
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Sugimoto, M. A., Vago, J. P., Teixeira, M. M., & Sousa, L. P. (2016) · Journal of Immunology Research · doi:10.1155/2016/8239258 · Cited by 414
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Resolution of inflammation is altered in Alzheimer's disease
Wang, X., Zhu, M., Hjorth, E., Cortés‐Toro, V., Eyjolfsdottir, H., Graff, C., Nennesmo, I., Palmblad, J., Eriksdotter, M., Sambamurti, K., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.12.024 · Cited by 301
Metadata
- Authors
- Maderna, P., Cottell, D. C., Toivonen, T., Dufton, N., Dalli, J., Perretti, M., & Godson, C.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2010-06-22
- Volume
- 24
- Issue
- 11
- Pages
- 4240-4249
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2148056149
- Cited by
- 180
- References
- 6
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- green
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