Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

Livne‐Bar, Izhar; Wei, Jessica; Liu, Hsin‐Hua; Alqawlaq, Samih; Won, Gah-Jone; Tuccitto, Alessandra; Gronert, Karsten; Flanagan, John G.; Sivak, Jeremy M.

doi:10.1172/jci77398

Cited by 75 publications

(116 citation statements)

References 81 publications

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“…2C, 2D). This preferential progression of ganglion cell dysfunction with longer periods of IOP elevation has also been noted in the rat circumlimbal suture model, 25 mouse circumlimbal suture model, 35,41 as well as the DBA2J mouse. 42 The data also suggest that there is variability in the contralateral control eye responses between groups (Fig.…”

Section: Discussionsupporting

confidence: 60%

Reversibility of Retinal Ganglion Cell Dysfunction From Chronic IOP Elevation

Zhao

Wong

Nguyen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Zhao D, Wong VHY, Nguyen CTO, et al. Reversibility of retinal ganglion cell dysfunction from chronic IOP elevation. Invest Ophthalmol Vis Sci. 2019;60:3878-3886. https:// doi.org/10.1167/iovs.19-27113 PURPOSE.To test the hypothesis that the capacity for retinal ganglion cells to functionally recover from chronic IOP elevation is dependent on the duration of IOP elevation.METHODS. IOP elevation was induced in one eye in anesthetized (isoflurane) adult C57BL6/J mice using a circumlimbal suture. Sutures were left in place for 8 and 16 weeks (n ¼ 30 and 28). In two other groups the suture was cut after 8 and 12 weeks (n ¼ 30 and 28), and ganglion cell function (electroretinography) and retinal structure (optical coherence tomography) were assessed 4 weeks later. Ganglion cell density was quantified by counting RBPMS (RNA-binding protein with multiple splicing)-stained cells. RESULTS.With IOP elevation (~10 mm Hg above baseline), ganglion cell function declined to 75% 6 8% at 8 weeks and 59% 6 4% at 16 weeks relative to contralateral control eyes. The retinal nerve fiber layer was thinner at 8 (84% 6 4%) and 16 weeks (83% 6 3%), without a significant difference in total retinal thickness. Ganglion cell function recovered with IOP normalization (suture removal) at week 8 (97% 6 7%), but not at week 12 (73% 6 6%). Ganglion cell loss was found in all groups (À8% to À13%). CONCLUSIONS.In the mouse circumlimbal suture model, 12 weeks of IOP elevation resulted in irreversible ganglion cell dysfunction, whereas retinal dysfunction was fully reversible after 8 weeks of IOP elevation.

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Section: Discussionsupporting

confidence: 60%

Reversibility of Retinal Ganglion Cell Dysfunction From Chronic IOP Elevation

Zhao

Wong

Nguyen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Vagus SPM from arachidonic acid included lipoxin A 4 and lipoxin B 4 [140]. Along with their ability to activate resolution [5], lipoxin A 4 reduces neuroinflammation and neuropathic pain following hemisection of spinal cord via reducing microglial activation [144], and both lipoxins (LXA 4 and LXB 4 ) are neuroprotective [145]. Thus, their production by human vagus, as well as the other SPM documented [140] via diagnostic MS-MS spectra and physical properties, is of interest as potential chemical mediators from vagal stimulation.…”

Section: Human Vagus and Lipid Mediatorsmentioning

confidence: 99%

Novel mediators and mechanisms in the resolution of infectious inflammation: evidence for vagus regulation

2019

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Excessive chronic inflammation is linked to many diseases and considered a stress factor in humans (Robbins Pathologic Basis of Disease. Philadelphia: W.B. Saunders Co., 1999, Proc Natl Acad Sci USA, 2008, 105: 17949, Immunity, 44, 2016, 44: 463, N Engl J Med, 2011, 364: 656). Today, the resolution of inflammation is widely recognized as a cellular biochemically active process involving biosynthesis of a novel superfamily of endogenous chemical signals coined specialized pro‐resolving mediators (SPMs; Nature, 2014, 510:92). Herein, we review recent evidence, indicating a role for the vagus nerve and vagotomy in the regulation of lipid mediators. Vagotomy reduces pro‐resolving mediators, including the lipoxins, resolvins, protectins and maresins, delaying resolution in mouse peritonitis. Vagotomy also delays resolution of Escherichia coli infection in mice. Specifically, right vagus regulates peritoneal Group 3 innate lymphoid cell (ILC‐3) number and peritoneal macrophage responses with lipid mediator profile signatures with elevated pro‐inflammatory eicosanoids and reduced resolvins, including the novel protective immunoresolvent agonist protectin conjugate in tissue regeneration1 (PCTR1). Acetylcholine upregulates PCTR biosynthesis, and administration of PCTR1 to vagotomized mice restores tissue resolution and host responses to E. coli infections. Results obtained with human vagus ex vivo indicate that vagus can produce both pro‐inflammatory eicosanoids, such as prostaglandins and leukotrienes, as well as the SPM. Electrical stimulation of human vagus in vitro reduces both prostaglandins and leukotrienes and enhances resolvins and the other SPM. These results elucidate a host protective mechanism mediated by vagus stimulation of SPM that includes resolvins and PCTR1 to regulate myeloid antimicrobial functions and resolution of infection. Moreover, they define a new pro‐resolution of inflammation reflex operative in mice and human tissue that involves a vagus SPM circuit.

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“…In experimental models of eye infections, LXA 4 concentrations were between 2‐ and 10‐fold higher than those of PGE 2 . The production of eicosanoids and SPM is also regulated in a sex‐dependent manner where LXA 4 concentrations in females were elevated when compared to males during experimental eye infections (Livne‐Bar et al ., ), whereas RvD and RvE are elevated during experimental inflammation in humans (Rathod et al ., ). The scope of the present review is to discuss the evidence underpinning the protective actions of SPM and how insights into their biological actions may provide leads on the utility of harnessing SPM as templates for the development of resolution pharmacology‐based therapeutics that would carry a lower burden of side effects.…”

mentioning

confidence: 99%

Identification and structure elucidation of the pro‐resolving mediators provides novel leads for resolution pharmacology

Dalli

Serhan

2018

British J Pharmacology

111

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Inflammatory diseases are a major socio‐economic burden, with the incidence of such conditions on the rise, especially in western societies. For decades, the primary treatment paradigm for many of these conditions was to develop drugs that inhibit or antagonize the production and biological actions of molecules that were thought to be the culprits in propagating disease; these include cytokines and eicosanoids. This approach is effective in controlling disease propagation; however, long‐term exposure to these anti‐inflammatories is also associated with many side effects, some of which are severe, including immune‐suppression. The discovery that termination of self‐limited acute inflammation is an active process orchestrated by endogenous mediators, including the essential fatty acid‐derived resolvins, protectins and maresins, has provided novel opportunities for the design of therapeutics that control inflammation with a lower burden of side effects. This is because at variance to anti‐inflammatories, pro‐resolving mediators do not completely inhibit inflammatory responses; instead, these mediators reprogramme the immune response to accelerate the termination of inflammation, facilitating the regain of function. The scope of this review is to highlight the biological actions of these autacoids and their potential utility as lead compounds in developing resolution pharmacology‐based therapeutics. Linked Articles This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc

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Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

Cited by 75 publications

References 81 publications

Reversibility of Retinal Ganglion Cell Dysfunction From Chronic IOP Elevation

Reversibility of Retinal Ganglion Cell Dysfunction From Chronic IOP Elevation

Novel mediators and mechanisms in the resolution of infectious inflammation: evidence for vagus regulation

Identification and structure elucidation of the pro‐resolving mediators provides novel leads for resolution pharmacology

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