Maresin 1 resolves aged‐associated macrophage inflammation to improve bone regeneration

Abstract

Inflammaging is associated with poor tissue regeneration observed in advanced age. Specifically, protracted inflammation after acute injury has been associated with decreased bone fracture healing and increased rates of nonunion in elderly patients. Here, we investigated the efficacy of using Maresin 1 (MaR1), an omega‐3 fatty acid‐derived pro‐resolving agent, to resolve inflammation after tibial fracture injury and subsequently improving aged bone healing. Aged (24‐month‐old mice) underwent tibial fracture surgery and were either treated with vehicle or MaR1 3 days after injury. Fracture calluses were harvested 7 days, 14 days, 21 days, and 28 days after injury to investigate inflammatory response, cartilage development, bone deposition, and mechanical integrity, respectively. Healing bones from MaR1‐treated mice displayed decreased cartilage formation and increased bone deposition which resulted in increased structural stiffness and increased force to fracture in the later stages of repair. In the early stages, MaR1 treatment decreased the number of pro‐inflammatory macrophages within the fracture callus and decreased the level of inflammatory biomarkers in circulation. In tissue culture models, MaR1 treatment of bone marrow‐derived macrophages from aged mice protected cells form a pro‐inflammatory phenotype and induced an anti‐inflammatory fate. Furthermore, the secretome of MaR1‐treated bone marrow‐derived macrophages was identified as osteoinductive, enhancing osteoblast differentiation of bone marrow stromal cells. Our findings here identify resolution of inflammation, and MaR1 itself, to be a point of intervention to improve aged bone healing.

The Proresolving Lipid Mediator Maresin1 Alleviates Experimental Pancreatitis via Switching Macrophage Polarization

“…Delayed administration for MaR1 may provide some hints about its effect on M2 macrophages. Further, like our results, some studies reported that MaR1 markedly decreased the number of proinflammatory macrophages, but not that of antiinflammatory macrophages in inflammation models [38,39]. In addition, MaR1 can enhance macrophage phagocytosis of neutrophils during inflammation.…”

“…Another problem is the timing of administration of MaR1 in mice. In the tibial fracture injury model, MaR1 treatment at the time of injury is ineffective in decreasing the number of proinflammatory macrophages, different from the treatment results after injury [38]. Macrophages exhibit dynamic transitions in phenotype and function as AP progresses.…”

Changes in brown adipose tissue lipid mediator signatures with aging, obesity, and DHA supplementation in female mice

“…26,65 MaR1 has been also shown to resolve agedassociated macrophage inflammation to improve bone regeneration. 66 However, the actions of MaR2 in brown/white adipose tissue are still unknown. Clària et al 23 found that 14-HDHA, a precursor of MaRs, was reduced in WAT of obese mice.…”

LGR6 is necessary for attaining peak bone mass and regulates osteogenesis through differential ligand use

“…It remains to be determined whether increased LGR6 activity in MSCs in vivo would result in increased bone production like we find in vitro (Figure 2 and Supplemental Figure 6), which could provide inroads to novel anabolic therapies. While the result of exogenous RSPO2 treatment on bone has not been reported, exogenous MaR1 has been associated with bone regeneration 24,34 . Exogenous MaR1 can stimulate bone formation in rat molar sockets and resolve macrophage based inflammation resulting in improved fracture healing in aged mice, though these studies did not explore LGR6 signaling 24,34 .…”