Effect of M2 Macrophage-Derived Soluble Factors on Behavioral Patterns and Cytokine Production in Various Brain Structures in Depression-Like Mice

Маркова, Е. В.; Shevela, Е. Ya.; Knyazeva, M. A.; Savkin, I.; Serenko, E. V.; Ращупкин, И. М.; Amstislavskaya, Tamara G.; Останин, А. А.; Черных, Е. Р.

doi:10.1007/s10517-022-05389-3

Cited by 7 publications

(5 citation statements)

References 15 publications

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“…Thus, despite the lack of an unambiguous view of the role of IGF-1 in the pathogenesis of depression, there is no doubt that this factor has a significant impact on the disease course. It is very likely that it is IGF-1 in the composition of the secretory product of macrophages M2(LS) that makes a significant contribution to the antidepressant effect of macrophages observed in the present and our previous studies [11].…”

Section: Resultssupporting

confidence: 58%

“…Previously, we revealed the ability of M2(LS) Mφ to enhance neurogenesis in vitro through stimula tion of proliferation, differentiation and survival of NSClike cells of the SH-SY5Y line [13]. Along with this, we observed a decrease in the concentration of proinflammatory cytokines (IL-1β and TNFα) in the brain of depression-like mice during intranasal therapy with soluble factors of M2(LS) [11], which indicates the anti-inflammatory activity of M2(LS) Mφ. Taken together, our data obtained earlier and presented in the current study indicate the neuroregenerative potential of macrophages polarized into the M2 phenotype by efferocytosis.…”

Section: Discussionmentioning

confidence: 52%

“…Anhedonia, decreased exploratory behavior, and social avoidance are observed in animals in this model. We have previously shown that intranasal administration of soluble factors derived from M2(LS) Mφ to depressionlike mice ameliorates behavioral pattern of animals, which was accompanied by a decrease in the level of pro-inflammatory cytokines in the brain [11]. The present study continues this line of work and focuses on the effect of M2(LS) Mφ on neuronal density in the frontal cortex and hippocampus of depressionlike mice.…”

Section: Introductionmentioning

confidence: 63%

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Effect of soluble factors of macrophages polarized by efferocytosis on neuronal density in the frontal cortex and hippocampus of mice in a model of stress-induced depression

Ращупкин

Amstislavskaya²,

Маркова

et al. 2023

Med. immunol.

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Recently, there has been a steady increase in depressive disorders, which occupy an important place in the structure of the causes of disability. In the pathogenesis of depression, an important role is played by neuroinflammation, which is associated with impaired adult neurogenesis. Notably, neuroinflammation is partially reversible, and the leading role in the initiation and regulation of neuroregeneration is given to macrophages. Opposite states of macrophage activation are classically activated M1 and alternatively activated M2 macrophages, characterized, respectively, by pro- and anti-inflammatory activity. A balance shift towards M2 macrophages has been considered as a new therapeutic strategy of psycho-neurological disorders. One of the inducers of the M2 phenotype is the efferocytosis. We have previously developed an original protocol for the generation of human macrophages under conditions of deficiency of growth / serum factors, in which M2 phenotype is formed through efferocytosis. Macrophages (M2(LS), LS – Low Serum) obtained according to this protocol express M2-associated markers, and are characterized by high production of growth and pro- angiogenic factors (IGF-1, VEGF, BDNF, EGF, FGF-basic, etc.), which can suppress inflammation and stimulate neuroregeneration / neuroplasticity. In the model of stress-induced depression, the antidepressant effect of soluble factors of M2(LS) macrophages was shown, accompanied by a decrease in the level of pro- inflammatory cytokines in certain brain structures. However, the effect of M2(LS) factors on neurogenesis remained unexplored. In the present work, which is a continuation of the aforementioned study, we analyzed the effect of intranasal administration of M2(LS) soluble factors on neuronal density in different brain areas – the frontal cortex and hippocampus – of depression-like mice. The results obtained showed that neuronal density in the frontal cortex, CA1 and CA3 zones of the hippocampus, was significantly higher in mice with intranasal administration of M2(LS) conditioned medium than in depression-like mice, and reached the level of neuronal density in intact animals. These results may indicate the neuroregenerative activity of M2(LS) macrophages in the model of stress-induced depression, which is mediated through soluble factors and manifests itself in an increase in the density of neurons in the brain.

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Section: Resultssupporting

confidence: 58%

Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 63%

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Effect of soluble factors of macrophages polarized by efferocytosis on neuronal density in the frontal cortex and hippocampus of mice in a model of stress-induced depression

Ращупкин

Amstislavskaya²,

Маркова

et al. 2023

Med. immunol.

Self Cite

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“…To investigate the therapeutic potential of human macrophages with the M2 phenotype, we designed an original protocol for obtaining M2-like macrophages from circulating monocytes based on their interaction with apoptotic cells [ 20 ]. Generated macrophages expressed M2-associated and pro-apoptogenic molecules; produced low levels of pro-inflammatory cytokines and a high concentration of TGF-b; were unable to stimulate effective T-lymphocyte proliferation and Th1/Th17 responses; produced various growth, neurotrophic, and angiogenic factors with higher levels of IGF-1, VEGF, and EPO as compared to M1 macrophages; and demonstrated neuroprotective and neuroregenerative activity in vitro and in vivo [ 20 , 21 , 22 ]. We evaluated these macrophages and their soluble factors in several pilot clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Intranasal Immunotherapy with M2 Macrophage Secretome Ameliorates Language Impairments and Autistic-like Behavior in Children

Shevela,

Loginova,

Munkuev

et al. 2024

JCM

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Background/Objectives: The intranasal delivery of various neurotropic substances is considered a new attractive therapeutic approach for treating neuropathologies associated with neuroinflammation and altered regeneration. Specific language impairment (SLI) that arises as a result of damage to the cortical speech zones during the developmental period is one of the most common problems in preschool children, and it is characterized by persistent difficulties in the acquisition, understanding, and use of language. This study’s objective is to evaluate the efficacy and safety of intranasal immunotherapy using the M2 macrophage secretome as a rich source of immunoregulatory and neurotrophic factors for the treatment of severe language impairment in children. Methods: Seventy-one children (54 boys and 17 girls, aged 3 to 13 years) were recruited to participate in a clinical trial (NCT04689282) in two medical centers. The children were examined before, 1 month after, and 6 months after the start of therapy. In the vast majority of children (55/71), language impairment was associated with autistic-like symptoms and attention deficit hyperactivity disorder (ADHD). Results: Daily intranasal inhalations of M2 macrophage-conditioned medium (for 30 days) were well tolerated and led to a decrease in the severity of language impairments, autistic-like behavior, and ADHD symptoms. The clinical effect appeared within a month after the first procedure and persisted or intensified during a 6-month follow-up. Two-thirds of the children showed a clear clinical improvement, while the rest had less pronounced improvement. Conclusions: Thus, the use of the M2 macrophage secretome and its intranasal delivery is safe, well tolerated, and clinically effective in children with severe language impairments.

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“…Pro-inflammatory cytokines promote increased corticosterone synthesis, decreased monoamine neurotransmitter synthesis, and increased reuptake [ 178 , 179 , 180 , 181 ]. Shevela et al reduced anxiety responses in mice in the field by intranasal delivery of soluble factors in M2 macrophage culture medium [ 182 ]. Concurrent studies have shown that M2 macrophages exert antidepressant potential by downregulating pro-inflammatory cytokines in the hippocampus, prefrontal cortex, and striatum.…”

Section: Intranasal Administration Of Antidepressant Active Ingredientsmentioning

confidence: 99%

Application of Intranasal Administration in the Delivery of Antidepressant Active Ingredients

et al. 2022

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As a mental disease in modern society, depression shows an increasing occurrence, with low cure rate and high recurrence rate. It has become the most disabling disease in the world. At present, the treatment of depression is mainly based on drug therapy combined with psychological therapy, physical therapy, and other adjuvant therapy methods. Antidepressants are primarily administered peripherally (oral and intravenous) and have a slow onset of action. Antidepressant active ingredients, such as neuropeptides, natural active ingredients, and some chemical agents, are limited by factors such as the blood–brain barrier (BBB), first-pass metabolism, and extensive adverse effects caused by systemic administration. The potential anatomical link between the non-invasive nose–brain pathway and the lesion site of depression may provide a more attractive option for the delivery of antidepressant active ingredients. The purpose of this article is to describe the specific link between intranasal administration and depression, the challenges of intranasal administration, as well as studies of intranasal administration of antidepressant active ingredients.

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Effect of M2 Macrophage-Derived Soluble Factors on Behavioral Patterns and Cytokine Production in Various Brain Structures in Depression-Like Mice

Cited by 7 publications

References 15 publications

Effect of soluble factors of macrophages polarized by efferocytosis on neuronal density in the frontal cortex and hippocampus of mice in a model of stress-induced depression

Effect of soluble factors of macrophages polarized by efferocytosis on neuronal density in the frontal cortex and hippocampus of mice in a model of stress-induced depression

Intranasal Immunotherapy with M2 Macrophage Secretome Ameliorates Language Impairments and Autistic-like Behavior in Children

Application of Intranasal Administration in the Delivery of Antidepressant Active Ingredients

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