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Posts Tagged ‘Airway’


Lipoxin A4 Regulates Natural Killer Cell in Asthma

Reporter: Larry H Bernstein, MD, FCAP

Lipoxin A4 Regulates Natural Killer Cell and Type 2 Innate Lymphoid Cell Activation in Asthma
 C Barnig, M Cernadas, S Dutile,…BR Levy.
Sci Transl Med  27 Feb 2013. ; 5(174): p. 174ra26  SciTranslMed.             http://dx.doi.org/10.1126/scitranslmed.3004812
Asthma is a prevalent disease of chronic inflammation in which
  • endogenous counterregulatory signaling pathways are dysregulated.
Recent evidence suggests that innate lymphoid cells (ILCs), including
  • natural killer (NK) cells and
  • type 2 ILCs (ILC2s),
    • can participate in the regulation of allergic airway responses,
    • in particular airway mucosal inflammation.
Sci Transl Med 27 February 2013:  5(174) 174ra26        http://dx.doi.org/10.1126/scitranslmed.3004812
Both NK cells and ILC2s expressed
  • the pro-resolving ALX/FPR2 receptors.
Lipoxin A4, a natural pro-resolving ligand for ALX/FPR2 receptors, significantly
  • increased NK cell–mediated eosinophil apoptosis and
  • decreased IL-13 release by ILC2s.
Together, these findings indicate that ILCs are targets for lipoxin A4
  • to decrease airway inflammation and mediate the catabasis of eosinophilic inflammation

Molecular biology for formyl peptide receptors in human diseases
Yongsheng Li , 

Leukocytes accumulate at sites of inflammation and immunological reaction in response to locally existing chemotactic mediators. The first chemotactic factors structurally defined were N-formyl peptides. Subsequently, numerous ligands were identified

FPRs interact with this menagerie of structurally diverse pro- and anti-inflammatory ligands to possess important regulatory effects in multiple diseases, including

  1. inflammation,
  2. amyloidosis,
  3. Alzheimer’s disease,
  4. prion disease,
  5. acquired immunodeficiency syndrome,
  6. obesity,
  7. diabetes, and
  8. cancer.

How these receptors recognize diverse ligands and how they contribute to disease pathogenesis and host defense are basic questions currently under investigation that

    • would open up new avenues for the future management of inflammation-related diseases.

FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis 
PMaderna, DC Cottell, T Toivonen, N Dufton, J Dalli, M Perretti and C Godson
The FASEB Journal Nov 2010; 24 (11): 4240-4249      Published online June 22, 2010, http://dx.doi.org/10.1096/fj.10-159913

Lipoxins (LXs) are endogenously produced eicosanoids with well-described anti-inflammatory and proresolution activities,

  • stimulating nonphlogistic phagocytosis of apoptotic cells by macrophages.

LXA4 and the glucocorticoid-derived annexin A1 peptide (Ac2–26) bind to a common G-protein-coupled receptor, termed FPR2/ALX. However, direct evidence of the involvement of FPR2/ALX in the anti-inflammatory and proresolution activity of LXA4 is still to be investigated. Here we describe FPR2/ALX trafficking in response to LXA4 and Ac2–26 stimulation. We have transfected cells with HA-tagged FPR2/ALX and studied receptor trafficking in unstimulated, LXA4 (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 LXA4 and Ac2–26 stimulated phagocytosis of apoptotic neutrophils.
  1. LXA4 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.
  2. Ac2–26 stimulates phagocytosis by BMDMs from wild-type mice 1.5-fold above basal (P<0.05), but  Ac2–26 failed to stimulate phagocytosis by BMDMs isolated from Fpr2−/− mice.

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.
http://www.FASEB.j.org/FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis.
We have transfected cells with HA-tagged FPR2/ALX and studied receptor trafficking in unstimulated, LXA4 (1–10 nM)- and Ac2–26 (30 μM)-treated cells using multiple approaches and 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 LXA4 and Ac2–26 stimulated phagocytosis of apoptotic neutrophils.

LXA4 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.

Ac2–26 stimulates phagocytosis by BMDMs from wild-type mice 1.5-fold above basal (P<0.05)

  •  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.
The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo.
Chiang, N., Serhan, CN, Dahlen, SE, Drazen, JM, Hay, DW, Rovati, GE, et al.
Pharmacol. Rev. 2006; 58, 463–487.      http://www.PharmacolRev.com/The_lipoxin_receptor_ALX:_potent_ligand_specific_and_stereoselective_actions_in_vivo/

Asthma Obstruction of the lumen of the bronchi...

Asthma Obstruction of the lumen of the bronchiole by mucoid exudate, goblet cell metaplasia, epithelial basement membrane thickening and severe inflammation of bronchiole. (Photo credit: Wikipedia)

Schematic diagram indicating the complementary...

Schematic diagram indicating the complementary activities of cytotoxic T-cells and NK cells. (Photo credit: Wikipedia)

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