Myeloid ALX/FPR2 regulates vascularization following tissue injury

Abstract

Ischemic injury initiates a sterile inflammatory response that ultimately participates in the repair and recovery of tissue perfusion. Macrophages are required for perfusion recovery during ischemia, in part because they produce growth factors that aid in vascular remodeling. The input signals governing this pro-revascularization phenotype remain of interest. Here we found that hindlimb ischemia increases levels of resolvin D1 (RvD1), an inflammation-resolving lipid mediator that targets macrophages via its receptor, ALX/FPR2. Exogenous RvD1 enhances perfusion recovery during ischemia, and mice deficient inAlx/Fpr2have an endogenous defect in this process. Mechanistically, RNA sequencing revealed that RvD1 induces a transcriptional program in macrophages characteristic of a pro-revascularization phenotype. Vascularization of ischemic skeletal muscle, as well as cutaneous wounds, is impaired in mice with myeloid-specific deficiency ofAlx/Fpr2, and this is associated with altered expression of pro-revascularization genes in skeletal muscle and macrophages isolated from skeletal muscle. Collectively, these results uncover a role of ALX/FPR2 in revascularization that may be amenable to therapeutic targeting in diseases associated with altered tissue perfusion and repair.

Resolvin D1 supports skeletal myofiber regeneration via actions on myeloid and muscle stem cells

“…25) in rat muscle 3 days after synergist ablation at levels ~2-fold higher than baseline. Nevertheless, Sansbury et al 2020 reported that RvD1 is indeed present within mouse skeletal muscle tissue, at very low concentrations (36).…”

Metabolipidomic profiling reveals an age‐related deficiency of skeletal muscle pro‐resolving mediators that contributes to maladaptive tissue remodeling

“…Specialized pro‐resolving mediators are produced in response to muscle injury (Giannakis et al, 2019; Markworth et al, 2020; Sansbury et al, 2020; Zhang et al, 2016) or physiological stress (Gangemi et al, 2003; Markworth et al, 2013; Vella et al, 2019; Zheng et al, 2019) implicating a role for these metabolites in muscle remodeling (Markworth et al, 2016). Current approaches to clinical management of soft tissue injuries focus predominantly on blocking cyclooxygenase (COX) mediated production of pro‐inflammatory prostaglandins with non‐steroidal anti‐inflammatory drugs (NSAIDs).…”

Local shifts in inflammatory and resolving lipid mediators in response to tendon overuse

“…Administration of resolution agonists, termed immunoresolvents, can limit inflammation and expedite its resolution, while simultaneously relieving pain and stimulating tissue repair 46 . Unlike NSAIDs that may interfere with musculoskeletal tissue remodeling, 26 remarkably immunoresolvents were recently found to rather exert overall pro‐regenerative actions following skeletal muscle injury 47‐52 …”