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Cutting edge: Parathyroid hormone facilitates macrophage efferocytosis in bone marrow via proresolving mediators resolvin D1 and resolvin D2.

ABSTRACT: Bone marrow macrophages stimulate skeletal wound repair and osteoblastic bone formation by poorly defined mechanisms. Specialized proresolving mediators of inflammation drive macrophage efferocytosis (phagocytosis of apoptotic cells) and resolution, but little is known regarding this process in the bone marrow. In this study, metabololipidomic profiling via liquid chromatography mass spectrometry revealed higher levels of specialized proresolving mediators in the bone marrow relative to the spleen. The endocrine and bone anabolic agent parathyroid hormone increased specialized proresolving mediator levels, including resolvins (Rvs), in bone marrow. Human and murine primary macrophages efferocytosed apoptotic osteoblasts in vitro, and RvD1 and RvD2 (10 pM-10 nM) enhanced this process. These findings support a unique profile of specialized lipid mediators in bone marrow that contribute to a feedback system for resolution of inflammation and maintenance of skeletal homeostasis.

SUBMITTER: McCauley LK

PROVIDER: S-EPMC4285693 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Cutting edge: Parathyroid hormone facilitates macrophage efferocytosis in bone marrow via proresolving mediators resolvin D1 and resolvin D2.

McCauley Laurie K LK Dalli Jesmond J Koh Amy J AJ Chiang Nan N Serhan Charles N CN

Journal of immunology (Baltimore, Md. : 1950) 20140602 1

Bone marrow macrophages stimulate skeletal wound repair and osteoblastic bone formation by poorly defined mechanisms. Specialized proresolving mediators of inflammation drive macrophage efferocytosis (phagocytosis of apoptotic cells) and resolution, but little is known regarding this process in the bone marrow. In this study, metabololipidomic profiling via liquid chromatography mass spectrometry revealed higher levels of specialized proresolving mediators in the bone marrow relative to the sple ...[more]

PMID: 24890726

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Project description:Resolvins D1 and D2 (RvDs) are structural isomers and metabolites of docosahexaenoic acid, an omega-3 fatty acid, enzymatically produced in our body in response to acute inflammation or microbial invasion. Resolvins have been shown to play an essential role in the resolution of inflammation, tissue repair, and return to homeostasis and thus are actively pursued as potential therapeutics in treating inflammatory disorders and infectious diseases. However, effective in vivo delivery of RvDs continues to be a challenging task. Recent studies demonstrated that RvD1 or RvD2 loaded in cell membrane-derived nanovesicles significantly increased therapeutic efficacy in treating murine peritonitis and ischemic stroke, respectively. The mechanistic details of how the subtle structural difference between RvD1 and RvD2 alters their molecular interactions with the membrane lipids of the nanovesicles and thus affects the loading efficiency remain unknown. Here, we report the encapsulation profiles of the neutral and ionized species of both RvD1 and RvD2 determined with the cell membrane-derived nanovesicles at pH values 5.4 and 7.4, respectively. Also, we performed microsecond time-scale all-atom molecular dynamics (MD) simulations in explicit water to elucidate the molecular interactions of both neutral and ionized species of RvD1 and RvD2 with the lipid bilayer using a model membrane system, containing 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and cholesterol. We found that the differences in the position and chirality of hydroxyl groups in RvD1 and RvD2 affected their location, orientation, and conformations within the bilayer. Surprisingly, the deprotonation of their carboxyl group caused their orientation and conformation to change from a fully extended one that is oriented in parallel to the membrane plane to a J-shaped bent conformation that is oriented perpendicular to the bilayer plane. Our studies offer valuable insight into the molecular interactions of RvD1/D2 with the lipid bilayer in atomistic details and provide a mechanistic explanation for the observed differences in the encapsulation profiles of RvD1 and RvD2, which may facilitate the rational design of nanovesicle-based therapeutics for treating inflammatory diseases.

Dataset Information

Cutting edge: Parathyroid hormone facilitates macrophage efferocytosis in bone marrow via proresolving mediators resolvin D1 and resolvin D2.

Publications

Cutting edge: Parathyroid hormone facilitates macrophage efferocytosis in bone marrow via proresolving mediators resolvin D1 and resolvin D2.

Similar Datasets

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