Immunomodulatory lipid mediator profiling of cerebrospinal fluid following surgery in older adults

Niccolò Terrando ,Pallavi Avasarala,John J Park ,Michael J Devinney ,Joseph P Mathew,Cliburn Chan,Mary Cooter,Krishna Rao Maddipati,Quintin J Quiñones ,Miles Berger

doi:10.1038/s41598-021-82606-5

Niccolò Terrando , Pallavi Avasarala + Show 8 more

Open Access

https://doi.org/10.1038/s41598-021-82606-5

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Abstract

Arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) derived lipids play key roles in initiating and resolving inflammation. Neuro-inflammation is thought to play a causal role in perioperative neurocognitive disorders, yet the role of these lipids in the human central nervous system in such disorders is unclear. Here we used liquid chromatography–mass spectrometry to quantify AA, DHA, and EPA derived lipid levels in non-centrifuged cerebrospinal fluid (CSF), centrifuged CSF pellets, and centrifuged CSF supernatants of older adults obtained before, 24 h and 6 weeks after surgery. GAGE analysis was used to determine AA, DHA and EPA metabolite pathway changes over time. Lipid mediators derived from AA, DHA and EPA were detected in all sample types. Postoperative lipid mediator changes were not significant in non-centrifuged CSF (p > 0.05 for all three pathways). The AA metabolite pathway showed significant changes in centrifuged CSF pellets and supernatants from before to 24 h after surgery (p = 0.0000247, p = 0.0155 respectively), from before to 6 weeks after surgery (p = 0.0000497, p = 0.0155, respectively), and from 24 h to 6 weeks after surgery (p = 0.0000499, p = 0.00363, respectively). These findings indicate that AA, DHA, and EPA derived lipids are detectable in human CSF, and the AA metabolite pathway shows postoperative changes in centrifuged CSF pellets and supernatants.

Highlights

Arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) derived lipids play key roles in initiating and resolving inflammation
For centrifuged cerebrospinal fluid (CSF) cell pellets, the AA mediators PGE2, LXA4, LTB4, 5(S),15(S)-DiHETE, 5(S),12(S)DiHETE, and 15-epi L XA4, the EPA mediator RvE2, and the DHA mediator 10S,17S-DiHDoHE were detectable at all time points (Supplemental Table 3)
We found that SPMs derived from the EPA, DHA, and AA pathways are detectable in centrifuged CSF supernatants, centrifuged CSF cell pellets, and noncentrifuged CSF samples obtained from older adults before and after surgery

Summary

Introduction

Arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) derived lipids play key roles in initiating and resolving inflammation. 5(S),15(S)-DiHETE (5S,6E,8Z,11Z,13E,15S)-5,15-Dihydroxyicosa-6,8,11,13-tetraenoic acid 5-HEPE (6E,8Z,11Z,14Z,17Z)-5-Hydroxyicosa-6,8,11,14,17-pentaenoic acid 5-HETE (5S,6E,8Z,11Z,14Z)-5-Hydroxyicosa-6,8,11,14-tetraenoic acid 7(S)-Maresin[1] (4Z,7S,8E,10E,12Z,14S,16Z,19Z)-7,14-Dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid 7-HDoHE (4Z,8E,10Z,13Z,16Z,19Z)-7-Hydroxydocosa-4,8,10,13,16,19-hexaenoic acid AA Arachidonic acid AD Alzheimer’s Disease AT-PD1 Aspirin triggered-protectin D1 AT-RvD1 Aspirin triggered-resolvin D1 AT-RvD3 Aspirin triggered-resolvin D3 CNS Central nervous system CSF Cerebrospinal fluid DHA Docosahexaenoic acid DMSO Dimethyl sulfoxide EPA Eicosapentaenoic acid FBS Fetal bovine serum GAGE Generally applicable gene-set enrichment LC–MS Liquid chromatography mass spectrometry LTB4 Leukotriene B4 LXA4 Lipoxin A4 LXA5 Lipoxin A5 LXB4 Lipoxin B4 MaR1 Maresin 1 MaR1(n-3,DPA) N-3 docosapentaenoic acid derived maresin 1 PD1 Protectin D1 PD1(n-3,DPA) N-3 docosapentaenoic acid derived protectin D1 PGD2 Prostaglandin D2 PGE2 Prostaglandin E2 PGF2a Prostaglandin F2alpha PNDs Perioperative neurocognitive disorders RvD1 Resolvin D1 RvD2 Resolvin D2 RvD3 Resolvin D3 RvD4 Resolvin D4 RvD5 Resolvin D5 RvD5(n-3,DPA) N-3 docosapentaenoic acid derived resolvin D5 RvD6 Resolvin D6 RvE1 Resolvin E1 RvE2 Resolvin E2 RvE3 Resolvin E3 SPM Specialized pro-resolving molecules TXB2 Thromboxane B2 Both animal and human studies show that peripheral tissue trauma induces a significant inflammatory response within the central nervous system[1,2,3,4]. We performed these measurements on non-centrifuged CSF, centrifuged CSF supernatants, and centrifuged CSF cell pellets to determine the extent to which these mediators are present in the cellular fraction versus aqueous phase of CSF

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