Τίτλος:
Lipid mediators and biomarkers associated with type 1 diabetes development
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Type 1 diabetes (T1D) is a consequence of autoimmune β cell destruction, but the role of lipids in this process is unknown. We previously reported that activation of Ca2+-independent phospholipase A2β (iPLA2β) modulates polarization of macrophages (MΦ). Hydrolysis of the sn-2 substituent of glycerophospholipids by iPLA2β can lead to the generation of oxidized lipids (eicosanoids), pro- and antiinflammatory, which can initiate and amplify immune responses triggering β cell death. As MΦ are early triggers of immune responses in islets, we examined the impact of iPLA2βderived lipids (iDLs) in spontaneous-T1D prone nonobese diabetic mice (NOD), in the context of MΦ production and plasma abundances of eicosanoids and sphingolipids. We find that (a) MΦNOD exhibit a proinflammatory lipid landscape during the prediabetic phase; (b) early inhibition or genetic reduction of iPLA2β reduces production of select proinflammatory lipids, promotes antiinflammatory MΦ phenotype, and reduces T1D incidence; (c) such lipid changes are reflected in NOD plasma during the prediabetic phase and at T1D onset; and (d) importantly, similar lipid signatures are evidenced in plasma of human subjects at high risk for developing T1D. These findings suggest that iDLs contribute to T1D onset and identify select lipids that could be targeted for therapeutics and, in conjunction with autoantibodies, serve as early biomarkers of pre-T1D. Copyright: © 2020, Nelson et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
Συγγραφείς:
Nelson, A.J.
Stephenson, D.J.
Bone, R.N.
Cardona, C.L.
Park, M.A.
Tusing, Y.G.
Lei, X.
Kokotos, G.
Graves, C.L.
Mathews, C.E.
Kramer, J.
Hessner, M.J.
Chalfant, C.E.
Ramanadham, S.
Εκδότης:
American Society for Clinical Investigation
Λέξεις-κλειδιά:
biological marker; calcium independent phospholipase A2; fatty acid; icosanoid; lipid; sphingolipid; 1,1,1-trifluoro-6-(naphthalen-2-yl)hexan-2-one; biological marker; fatty acid; icosanoid; ketone; lipid; naphthalene derivative; phospholipase A2 group IV, animal experiment; animal model; animal tissue; Article; controlled study; female; insulin dependent diabetes mellitus; intracellular signaling; lipid analysis; lipid blood level; lipidomics; macrophage function; macrophage production; molecular pathology; mouse; nonhuman; predictive value; protein expression; protein function; adolescent; animal; blood; C57BL mouse; child; drug effect; human; insulin dependent diabetes mellitus; lipid metabolism; male; metabolism; nonobese diabetic mouse; pathology; peritoneum macrophage; transplantation, Adolescent; Animals; Biomarkers; Child; Diabetes Mellitus, Type 1; Eicosanoids; Fatty Acids; Female; Group IV Phospholipases A2; Humans; Ketones; Lipid Metabolism; Lipids; Macrophages, Peritoneal; Male; Mice, Inbred C57BL; Mice, Inbred NOD; Naphthalenes
DOI:
10.1172/jci.insight.138034
