Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via ALX/FPR2 Receptor-Regulated MicroRNAs

Abstract

Remote damage is a secondary phenomenon that usually occurs after a primary brain damage in regions that are distant, yet functionally connected, and that is critical for determining the outcomes of several CNS pathologies, including traumatic brain and spinal cord injuries. The understanding of remote damage-associated mechanisms has been mostly achieved in several models of focal brain injury such as the hemicerebellectomy (HCb) experimental paradigm, which helped to identify the involvement of many key players, such as inflammation, oxidative stress, apoptosis and autophagy. Currently, few interventions have been shown to successfully limit the progression of secondary damage events and there is still an unmet need for new therapeutic options. Given the emergence of the novel concept of resolution of inflammation, mediated by the newly identified ω3-derived specialized pro-resolving lipid mediators, such as resolvins, we reported a reduced ability of HCb-injured animals to produce resolvin D1 (RvD1) and an increased expression of its target receptor ALX/FPR2 in remote brain regions. The in vivo administration of RvD1 promoted functional recovery and neuroprotection by reducing the activation of Iba-1+ microglia and GFAP+ astrocytes as well as by impairing inflammatory-induced neuronal cell death in remote regions. These effects were counteracted by intracerebroventricular neutralization of ALX/FPR2, whose activation by RvD1 also down-regulated miR-146b- and miR-219a-1-dependent inflammatory markers. In conclusion, we propose that innovative therapies based on RvD1-ALX/FPR2 axis could be exploited to curtail remote damage and enable neuroprotective effects after acute focal brain damage.

Docosahexaenoic acid, 22:6n‐3: Its roles in the structure and function of the brain

“…The neuroprotectors, resolvin D1, and aspirin‐triggered resolvin D1 improve brain functions and impair neuronal death by downregulating NF‐kB, TLR4, CD200, and IL6R (Bisicchia et al, 2018; Recchiuti et al, 2010). They induce remote functional recovery after brain damage (Bisicchia et al, 2018).…”

“…The neuroprotectors, resolvin D1, and aspirin‐triggered resolvin D1 improve brain functions and impair neuronal death by downregulating NF‐kB, TLR4, CD200, and IL6R (Bisicchia et al, 2018; Recchiuti et al, 2010). They induce remote functional recovery after brain damage (Bisicchia et al, 2018). Resolvin D2 and aspirin‐triggered resolvin D2 protect from cerebral ischemic injury through ERK1/2 phosphorylation followed by stimulation of nNOS or eNOS to inhibit programmed neuronal cell death and increase zonula occludens‐1 for the maintenance of blood‐brain barrier integrity (Zuo et al, 2018).…”

How to reprogram microglia toward beneficial functions

“…Although microglia express a wide range of lipid‐sensitive receptors and lipid metabolism‐related genes (Mauerer, Walczak, & Langmann, ; Mecha et al, ), the molecular link between bioactive fatty acids and their effects in microglia has not been completely clarified yet. Emerging evidence suggests that PUFAs can drive a protective phenotype through the activation of CB2, which is among microglial receptors reprogramming microglia toward beneficial function (Guida et al, ; Mecha et al, ; Nunez et al, ) but other receptors may be involved including ALX/FPR2 receptors (Bisicchia et al, ) (Figure ).…”

Impairment of DHA synthesis alters the expression of neuronal plasticity markers and the brain inflammatory status in mice

“…Of note, whether such DHA‐induced neuroprotective effects are mediated by this fatty acid alone or by its derived and specialized pro‐resolving mediators (SPMs) have yet to be unraveled. The discoveries that several DHA‐derived SPMs, such as resolvins or neuroprotectins, play critical roles in modulating microglia responses as well ad in the modulation of reactive species is suggestive of their possible involvement in controlling neuroplasticity and in representing a link between the immune and the central nervous systems. In addition, our findings show that even in the absence of inflammatory stimuli or without the induction of specific diseases, systemic DHA deficiency induces a basal inflammatory activity, which is characterized by an overall upregulation of several inflammatory markers; however, this only has a little impact on behavioral functions.…”

“…Moreover, the role of DHA in inflammation is already consolidated and is receiving greater attention mainly due to the discovery that it serves as a metabolic precursor for a new genus of anti‐inflammatory molecules, that is, resolvins, neuroprotectins, and maresins, that are involved in the spontaneous but active process of resolution of inflammation, which mainly involves myeloid cells such as macrophages and glial cells . Indeed, we have recently shown that the impairment of systemic DHA synthesis in Elovl2 −/− mice, delineates an immunophenotypical alteration of M1/M2 macrophages, with M1 being more pro‐inflammatory and M2 less protective, supporting the view that DHA has a relevant role in controlling inflammatory responses .…”