Plasticity of Leukocytic Exudates in Resolving Acute Inflammation Is Regulated by MicroRNA and Proresolving Mediators

Abstract

SUMMARY The magnitude and duration of acute inflammation are controlled by active resolution programs involving specialized proresolving mediators (SPMs; resolvins and maresins) and microRNAs (miRNAs). Here, we report that miR-466l was temporally regulated in murine exudate-infiltrating leukocytes. Neutrophil miR-466l overexpression in vivo promoted initiation of inflammation that anteceded macrophage expression of this miRNA, which accelerated resolution when overexpressed. In macrophages, miR-466l overexpression increased prostanoids and SPMs (e.g., resolvin D1 [RvD1] and RvD5), which enhanced resolution. RvD1, RvD2, maresin 1 (MaR1), and apoptotic neutrophils reduced miR-466l expression within human macrophages, a feedback regulation that most likely prepares for homeostasis. miR-466l was upregulated in peripheral blood of sepsis patients, and its increase correlated with nonsurvival from sepsis. SPMs and miR-466l regulated transcription factors activator protein 1 and nuclear factor κB1 in miRNA biogenesis. These results demonstrate pivotal roles for SPMs and miR-466l in dynamic leukocyte plasticity during resolution of acute inflammatory responses.

IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury

“…Whether this is due to either direct or indirect effects of IL-4 on macrophages is not known. In line with these results, we also found that the clearance of neutrophils from the injured spinal cord, which is a key step in the resolution of inflammation (Li et al 2013;Schwab et al 2007;Serhan 2014), was markedly accelerated after delayed IL-4 injection, linking the lack of IL-4 with a deficit in resolution of inflammation after SCI.…”

“…A variant activated form of macrophage was reported recently in the resolution phase of inflammation elicited by intraperitoneal administration of zymozan (Bystrom et al 2008;Stables et al 2011). These macrophages, referred to as "resolution-phase" macrophages express a mixed M1/M2 phenotype (expressing MHCII but lacking CD11c expression) (Bystrom et al 2008;Li et al 2013;Stables et al 2011), like the new macrophage subset we see in the spinal cord after delayed IL-4 injection.…”

“…In addition, these cells were reported to express anti-inflammatory cytokines as well as lipoxygenase (LOX) and cyclooxygenase (COX-2), key enzymes in the synthesis of the specialized pro-resolving lipid mediators, which turn on the resolution programs of inflammation (Bystrom et al 2008;Li et al 2013;Schwab et al 2007;Serhan 2014). We therefore assessed whether the new macrophage subset found after delayed IL-4 injection also displayed these resolution-phase markers.…”

MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis

“…This concept aligns with previous studies showing that (a) engagement of MerTK by apoptotic cells or other activators can activate both antiinflammatory and proresolving pathways (6)(7)(8)(30)(31)(32); and (b) proresolving mediators can promote MerTK expression and efferocytosis (7,33,34). Thus, when MerTK is rendered inactive by proteolytic cleavage, not only is there a defect in efferocytosis, but positive-feedback signaling in resolution is impaired, leading to loss of resolving mediators and further defects in efferocytosis.…”

MicroRNA-181b Regulates ALX/FPR2 Receptor Expression and Proresolution Signaling in Human Macrophages

“…In addition, Fredman et al (34) compared microRNA expression in self-limited and delayed zymosan-induced inflammation, finding that the RvD1-regulated mir-208 was expressed to a lower extent in exudates from delayed resolution inflammation. Moreover, Li et al (35) found that miR-466l is temporally regulated during inflammation resolution and enhances resolution by increasing RvD1 levels in mouse exudate-infiltrating leukocytes.…”