The Neuropeptide α-Melanocyte–Stimulating Hormone Prevents Persistent Corneal Edema following Injury

Alemi, Hamid; Wang, Shudan; Blanco, Tomas; Kahale, Francesca; Singh, Rohan B.; Ortiz, Gustavo; Musayeva, Aytan; Yuksel, Erdem; Pang, Kunpeng; Deshpande, Neha; Dohlman, Thomas H.; Jurkunas, Ula V.; Yin, Jia; Dana, Reza

doi:10.1016/j.ajpath.2023.09.007

Cited by 7 publications

(12 citation statements)

References 64 publications

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“…In this case, it cannot be overlooked that GPS1573 retains some antagonist effect on the MSH receptors: MC3R, MC4R and MC5R, but not on MC1R ( 60 ). This may, at least partially, explain the GPS-induced upregulation of PMN numbers, as it was previously observed that α-MSH, upon binding to MC4R and MC5R, inhibited the IL-8-induced neutrophil migration in vitro , and reduced the neutrophil migration to the site of inflammation in vivo ( 61 – 63 ). Moreover, the GPS-induced reduction in cortisol synthesis in stressed fish could be associated with high levels of catecholamines as it is known that the phenylethanolamine-N-methyl transferase (PNMT), which catalyzes the transformation of noradrenaline to adrenaline, is formed only in the presence of high local concentrations of cortisol ( 64 ).…”

Section: Discussionmentioning

confidence: 52%

Evolutionarily conserved mechanisms regulating stress-induced neutrophil redistribution in fish

Klak,

Maciuszek,

Pijanowski

et al. 2024

Front. Immunol.

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IntroductionStress may pose a serious challenge to immune homeostasis. Stress however also may prepare the immune system for challenges such as wounding or infection, which are likely to happen during a fight or flight stress response.MethodsIn common carp (Cyprinus carpio L.) we studied the stress-induced redistribution of neutrophils into circulation, and the expression of genes encoding CXC chemokines known to be involved in the regulation of neutrophil retention (CXCL12) and redistribution (CXCL8), and their receptors (CXCR4 and CXCR1-2, respectively) in blood leukocytes and in the fish hematopoietic organ – the head kidney. The potential involvement of CXC receptors and stress hormone receptors in stress-induced neutrophil redistribution was determined by an in vivo study with selective CXCR inhibitors and antagonists of the receptors involved in stress regulation: glucocorticoid/mineralocorticoid receptors (GRs/MRs), adrenergic receptors (ADRs) and the melanocortin 2 receptor (MC2R).ResultsThe stress-induced increase of blood neutrophils was accompanied by a neutrophil decrease in the hematopoietic organs. This increase was cortisol-induced and GR-dependent. Moreover, stress upregulated the expression of genes encoding CXCL12 and CXCL8 chemokines, their receptors, and the receptor for granulocytes colony-stimulation factor (GCSFR) and matrix metalloproteinase 9 (MMP9). Blocking of the CXCR4 and CXCR1 and 2 receptors with selective inhibitors inhibited the stress-induced neutrophil redistribution and affected the expression of genes encoding CXC chemokines and CXCRs as well as GCSFR and MMP9.DiscussionOur data demonstrate that acute stress leads to the mobilization of the immune system, characterized by neutrophilia. CXC chemokines and CXC receptors are involved in this stress-induced redistribution of neutrophils from the hematopoietic tissue into the peripheral blood. This phenomenon is directly regulated by interactions between cortisol and the GR/MR. Considering the pivotal importance of neutrophilic granulocytes in the first line of defense, this knowledge is important for aquaculture, but will also contribute to the mechanisms involved in the stress-induced perturbation in neutrophil redistribution as often observed in clinical practice.

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Section: Discussionmentioning

confidence: 52%

Evolutionarily conserved mechanisms regulating stress-induced neutrophil redistribution in fish

Klak,

Maciuszek,

Pijanowski

et al. 2024

Front. Immunol.

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“…Stimulated ARPE-19 cells treated with α-MSH are suppressed in the production of monocyte chemotactic protein 1 and induce anti-oxidative enzyme activity in primary RPE exposed to high glucose [17,53,54]. Treatment of human corneal buttons for transplantation retains epithelial cells with less cell death [16]. The neuropeptide prevents apoptosis in cultured macrophages and RPE cells [17,55].…”

Section: Discussionmentioning

confidence: 99%

“…Immune cells, when treated with α-MSH, after being stimulated by factors that promote inflammation, produce anti-inflammatory cytokines, suppress inflammation, and mediate immune tolerance [15]. Besides the suppression of inflammation, α-MSH rescues cells from apoptosis [14,[16][17][18][19][20]. Diabetic mice and rats treated with α-MSH or melanocortin receptor agonists have suppressed pathology and cytokines of diabetic retinopathy, including the retention of viable photoreceptors and ganglion cells [20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Alpha-Melanocyte-Stimulating Hormone Maintains Retinal Homeostasis after Ischemia/Reperfusion

Ng,

Cho,

Zhao

et al. 2024

Biomolecules

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Augmenting the natural melanocortin pathway in mouse eyes with uveitis or diabetes protects the retinas from degeneration. The retinal cells are protected from oxidative and apoptotic signals of death. Therefore, we investigated the effects of a therapeutic application of the melanocortin alpha-melanocyte-stimulating hormone (α-MSH) on an ischemia and reperfusion (I/R) model of retinal degenerative disease. Eyes were subjected to an I/R procedure and were treated with α-MSH. Retinal sections were histopathologically scored. Also, the retinal sections were immunostained for viable ganglion cells, activated Muller cells, microglial cells, and apoptosis. The I/R caused retinal deformation and ganglion cell loss that was significantly reduced in I/R eyes treated with α-MSH. While α-MSH treatment marginally reduced the number of GFAP-positive Muller cells, it significantly suppressed the density of Iba1-positive microglial cells in the I/R retinas. Within one hour after I/R, there was apoptosis in the ganglion cell layer, and by 48 h, there was apoptosis in all layers of the neuroretina. The α-MSH treatment significantly reduced and delayed the onset of apoptosis in the retinas of I/R eyes. The results demonstrate that therapeutically augmenting the melanocortin pathways preserves retinal structure and cell survival in eyes with progressive neuroretinal degenerative disease.

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“…Optical coherence tomography (OCT) imaging was performed after slit lamp examination. As per our established protocol [ 38 , 39 ], the mice were anesthetized with ketamine/xylazine, and topical anesthesia using 0.5% proparacaine ophthalmic solution (1–2 drops) was applied to both eyes. For the evaluation of changes in the epithelial layer and central corneal thickness, we utilized an anterior segment optical coherence tomography (AS-OCT) system (Bioptigen Spectral Domain Ophthalmic Imaging System Envisu R2200) equipped with a 12-mm telecentric cornea lens.…”

Section: Methodsmentioning

confidence: 99%

“…The images were obtained in an area of 400 × 400 μm, with a transverse optical resolution of approximately 1 mm/pixel of all the different layers of the cornea. The epithelium and sub-basal nerves were subjectively evaluated, while both the subepithelial dendritic cell and endothelial cell density (cells/mm 2 ) were quantified in each frame using built-in software [ 38 , 39 ].…”

Section: Methodsmentioning

confidence: 99%

Effects of Diabetes Mellitus on Corneal Immune Cell Activation and the Development of Keratopathy

Surico,

Narimatsu,

Forouzanfar

et al. 2024

Cells

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Diabetes mellitus (DM) is one of the most prevalent diseases globally, and its prevalence is rapidly increasing. Most patients with a long-term history of DM present with some degree of keratopathy (DK). Despite its high incidence, the underlying inflammatory mechanism of DK has not been elucidated yet. For further insights into the underlying immunopathologic processes, we utilized streptozotocin-induced mice to model type 1 DM (T1D) and B6.Cg-Lepob/J mice to model type 2 DM (T2D). We evaluated the animals for the development of clinical manifestations of DK. Four weeks post-induction, the total frequencies of corneal CD45+CD11b+Ly-6G− myeloid cells, with enhanced gene and protein expression levels for the proinflammatory cytokines TNF-α and IL-1β, were higher in both T1D and T2D animals. Additionally, the frequencies of myeloid cells/mm2 in the sub-basal neural plexus (SBNP) were significantly higher in T1D and T2D compared to non-diabetic mice. DK clinical manifestations were observed four weeks post-induction, including significantly lower tear production, corneal sensitivity, and epitheliopathy. Nerve density in the SBNP and intraepithelial terminal endings per 40x field were lower in both models compared to the normal controls. The findings of this study indicate that DM alters the immune quiescent state of the cornea during disease onset, which may be associated with the progressive development of the clinical manifestations of DK.

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The Neuropeptide α-Melanocyte–Stimulating Hormone Prevents Persistent Corneal Edema following Injury

Cited by 7 publications

References 64 publications

Evolutionarily conserved mechanisms regulating stress-induced neutrophil redistribution in fish

Evolutionarily conserved mechanisms regulating stress-induced neutrophil redistribution in fish

Alpha-Melanocyte-Stimulating Hormone Maintains Retinal Homeostasis after Ischemia/Reperfusion

Effects of Diabetes Mellitus on Corneal Immune Cell Activation and the Development of Keratopathy

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