Understanding How Allergic Responses End: The Allergy Resolvome Lipid mediators Koichiro Asano Tokai University School of Medicine, Kanagawa, JAPAN ko-asano@tokai-u.jp
Resolution of granulocytic inflammation Front. Immun. 3: 27, 212
COX- 2 Arachidonic acid 15- LO!ish oil ω3- fajy acid EPA DHA Prostagrandin 5- LO 5- LO Acetylated COX- 2 15- LO Leukotriene A4 12- LO Lipoxin A4 Resolvin E1 ProtecEn D1 LTB4 Cys LTs anti-inflammatory pro-resolving mediators pro-inflammatory mediators Pro- and anti-inflammatory lipid mediators
Receptors for lipid mediators Resolvin E4 Lippoxin A4 Leukotrien B4 Cysteinyl leukotriens Prostaglandins
Specialized Pro-resolving lipid Mediators (SPM) Lipoxins (LX) LXA 4 /LXB 4 15-epi-LXA 4 /15-epi-LXB 4 Protectins (PD) PD1 Resolvins (Rv) E series (RvE1/RvE2/RvE3) D series (RvD1) Maresins (MaR) MaR1 1. Synthetic pathway 2. Receptor 3. Bioactivity (in vitro) 4. Bioactivity in the airways 5. Relationship with pathophysiology of severe asthma
Lipoxin A4 Arachidonic acid 15- LO (12- LO) 15- LO 15(S)- HpETE 15- LO 5- LO 15(R)- HETE 15- HETE Lipoxin A4 Aspirin + Cox- 2 15- epi- Lipoxin A4
Lipoxin A4 receptors Chiang et al. Pharmacol Rev. 58: 463, 26
Bioactivity of Lipoxin A4 Neutrophils = anti-inflammation block migration block O 2 - generation block degranulation Monocytes = pro-resolution enhance chemotaxis stimulate phagocytosis of apoptotic PMNs Nature Reviews Immunology 8, 349, 28
Bioactivity of Lipoxin A4 Neutrophils = anti-inflammation block migration block O 2 - generation block degranulation Monocytes = pro-resolution enhance chemotaxis stimulate phagocytosis of apoptotic PMNs Eosinophils block migration do not block degranulation do not block Ca 2+ influx Airway epithelial cells cell proliferation increase epithelial barrier function tight junction expression of bactericidal/permeability-increasing protein (BPI)
Bioactivity of Lipoxin A4 Group 2 Innate lymphoid cell = anti-inflammation block IL-13 synthesis NK cells = pro-resolution enhance the activity to induce apoptosis in eosinophils Group 2 ILCs Natural helper cell: Moro K. et al. Nature 21 463. MPP type2 : Saenz SA. et al. Nature 21 464. Nuocyte : Neill DR. et al. Nature 21 464. Spits et al. Nat Rev Immunol, 13: 145, 213
Bioactivity of Lipoxin A4 in the airways Block LTC4-induced bronchoconstriction Christie et al. Am Rev Respir Dis. 145:1281, 1992 Suppress allergen-induced pleurisy in mice suppress eosinophil infiltration suppress IL-5 expression suppress eotaxin expression Bandeira-Melo, et al. J Immunol 164:2267, 2 Suppress allergen-induced airway inflammation in mice suppress eosinophil infiltration suppress bronchial hyperresponsiveness suppress IL-4, IL-5, IL-13 expression not mediated by the inhibition of cyslt1r Levy, et al. Nat Med 8: 118, 22 Levy, et al. FASEB J 21:3877, 27
Lipoxin A4 in severe asthma Whole blood cells stimulated with Ca 2+ ionophore Levy et al. Am J Respir Crit Care Med. 172:824, 25 Celik, et al. Clin Exp Allergy 37:1494, 27 Induced sputum Vachier, et al. J Allergy Clin Immunol. 115:55, 25 Exhaled breath condensate Kazani et al. J Allergy Clin Immunol. 132:547, 213 Bronchoalveolar lavage fluid Planagumà et al. Am J Respir Crit Care Med. 178:574, 28
Lipoxin A4 in severe asthma Severe asthma vs. mild-moderate asthma Lipoxin A4 15-epi- LxA4 15-HETE LTs LTs/LxA4 Stimulated peripheral blood cells Stimulated peripheral blood cells Induced sputum Exhaled breath condensate BAL
Resolvin E1 Receptors ChemR23 BLT1 Bioactivities Neutriphils block migration block O 2 - generation Monocytes stimulate phagocytosis of apoptotic PMNs
Bioactivity of Resolvin E1 in the airways Suppress allergen-induced airway inflammation in mice suppress eosinophil infiltration suppress bronchial hyperresponsiveness suppress IL-13 expression (no data on IL-4, IL-5) suppress IL-6, IL-17, IL-23 expression when administered during resolution phase Increase IFN-γ and Lipoxin A4 levels Aoki, et al. Biochem Biophys Res Commun 367: 59, 28 Haworth, et al. Nat Immunol 9: 873, 28 Sensitization Allergen exposure
Protectin D1 (Neuroprotectin D1) Serhan CN, et al. Chem Rev 211
Bioactivity of protectin D1 neuroprotection inhibits neutrophil migration reduces cytokine synthesis in glial cells inhibition of retinal and corneal injury improves wound healing inhibition of eosinophil migration suppress chemotaxis suppress the expression of adhesion molecules J. Miyata, K. Asano et al. J Allergy Clin Immunol 131:353-6, 213
Bioactivity of Protectin D1 in the airways OVA-sensitized/challenged mice Protectin D1 suppresses eosinophil accumulation bronchial hyperresponsiveness IL13 expression cyslt synthesis PD1 2 ng PD1 2 ng PD1 2 ng vehicle Levy, et al. J Immunol 178: 496, 27
Protectin D1 and asthma exacerbation 5 p <.5 4 PD1 in EBC (ng/ml) 3 2 1 Healthy control trace amounts Asthma exacerbation Levy, et al. J Immunol 178: 496, 27
Eosinophils and eosinophil-derived lipid mediators as a negative regulator of inflammation infection tissue damage time Yamada T et al. FASEB J 211
Class switching in the lipid metabolome Cyclooxygenase-2 (Cox-2) 5-lipoxigenase (5-LO) 12-lipoxygease (12-LO) 15-lipoxygenase (15-LO) J Immunol. 211 Oct 1;187(7):3475
Lipidomic analysis of eosinophil-derived lipid mediators LC-MS/MS (Liquid chromatography/tandem mass spectrometry)
Lipidomic analysis of eosinophil-derived lipid mediators and severe asthma J. Miyata, K. Asano et al. J Allergy Clin Immunol 131:353-6, 213
Lipidomic analysis of eosinophil-derived lipid mediators and severe asthma 14 12 1 8 6 4 2 7 6 5 4 3 TxB 2 PGD 2 12-HHT Decrease in cyclooxygenase products 3 12 25 1 2 8 15 6 5,6-EET 8,9-EET PGE2 7% TxB2 26% 1 4 7 18 4 5 2 6 16 35 14 5 3 12 25 4 1 2 3 8 15 PGH 2 COX 6 AA P45 2 4 1 1 2 5 5-LO 12/15-LO LTA 4 11,12-EET 7 6 5 4 3 2 1 14,15-EET 2 1 25 2 15 1 5 3 25 2 15 1 5 PGE 2 PGF 2α 16 14 12 1 8 6 4 2 18 16 14 12 1 8 6 4 2 LTB 4 LTB 4-2OH 14 12 1 8 6 4 2 5 45 4 35 3 25 2 15 1 5 5-HETE 5-oxo-ETE 12 1 8 6 4 2 3 25 2 15 1 5 12-HETE 12-oxo-ETE 14 12 1 8 6 4 2 6 5 4 3 2 1 15-HETE 15-oxo-ETE 18 16 14 12 1 8 6 4 2 35 3 25 2 15 1 5 LXA 4 5,15-diHETE 9 8 7 6 5 4 3 2 1 14,15-DHT Sample EOS 5x1^5 cells! A23187!! healthy subject severe asthmatic 6-keto-PGF 1α 3 3 2 2 1 1 2 No change in 5-lipoxygenase products 15 1 5 Decrease in 12/15-lipoxygenase products 8-HETE 9-HETE 11-HETE 16-HETE 17-HETE 18 9 3 16 4 4 16 8 14 4 4 25 14 7 12 3 3 12 6 2 1 3 3 1 5 15 8 2 2 8 4 6 2 2 6 3 1 4 2 4 1 1 5 2 1 2 1 1 18-HETE 35 3 25 8,15-diHETE 5 45 4 35 3 25 2 15 1 5 19-HETE 3 25 2 15 1 5 pg/sample! N=4 mean ± S.E. 2-HETE
RvE1 improves survival after aspiration pneumonia without compromising host defense against infection % Survival 1 75 5 25 RvE1 No treatment * Colony count 6 3 Bacterial growth 1 2 3 4 5 6 7 Time a]er E. coli inoculaeon (d).1 1 1 1 RvE1 (nm) Seki, Fukunaga, Asano et al. J Immnol, 211
Antimicrobial Aspects of Inflammatory Resolution in the Mucosa J Immunol. 211 Oct 1;187(7):3475