Comparative analysis of decidual and peripheral immune cells and immune‐checkpoint molecules during pregnancy in wild‐type and PACAP‐deficient mice

Lajko, Adrienn; Meggyes, Mátyás; Fülöp, B; Gede, Noémi; Reglődi, Dóra; Szereday, László

doi:10.1111/aji.13035

Cited by 13 publications

(11 citation statements)

References 38 publications

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“…Interestingly, the Gal-9 expression at the maternal-fetal interface was decreased in the LPS-treated group and was rescued after exogenous administration of Gal-9 arriving at the similar level as observed in the control group. Moreover, Gal-9 protein was mainly localized at one pole of embryo implantation at E9 and in the spongiotrophoblast layer and decidua at E20, which was consistent with other study (63). It is known that the trophoblast cells in the spongiotrophoblast layer have the invasive function.…”

Section: Discussionsupporting

confidence: 92%

Galectin-9 Alleviates LPS-Induced Preeclampsia-Like Impairment in Rats via Switching Decidual Macrophage Polarization to M2 Subtype

Wang

Luan

et al. 2019

Front. Immunol.

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Dysfunction of decidual macrophages (DMs) is considered a critical event in the pathogenesis of pre-eclampsia (PE). T cell immunoglobulin mucin 3 (Tim-3) is an important negative regulatory molecule that induces immune tolerance by interacting with its ligand Galectin-9 (Gal-9) and thus modulating function of various immune cells, including macrophages. However, the regulatory effects of Tim-3/Gal-9 signaling on DMs polarization and its role in PE remain unclear. In this study, we established a PE-like rat model by administering 1.0 μg/kg lipopolysaccharide (LPS) to normal pregnant Sprague-Dawley rats via the tail vein at embryonic day 5 (E5). Apart from the pre-eclamptic manifestations, increased M1 subtype and decreased M2 subtype were observed at the maternal-fetal interface, as well as increased pro-inflammatory cytokines (TNF-α and IL-1β) and reduced anti-inflammatory cytokines (TGF-β and IL-10). Moreover, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were reduced. After administration of recombinant Galectin-9 (rGal-9) protein, we found that liver and renal injuries and maternofetal placental functional deficiency, including inadequate trophoblast cells invasion, impaired spiral artery remodeling and fetal capillary development, were reversed. In addition, the polarization of DMs was inclined to M2 subtype, which was similar to the polarization of DMs in the control rats but contrary to the PE-like rats. Interestingly, at E9, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were significantly increased in the rGal-9 protein intervention group. Taken together, our findings show that administration of rGal-9 protein can alleviate the PE-like rat manifestations induced by LPS. This finding may be related to the activation of the Tim-3/Gal-9 signaling pathway, which promotes DMs polarization dominantly shifting to M2 subtype. Moreover, upregulation of Tim-3 in DMs and Gal-9 at the maternal-fetal interface at E9 suggests that Tim-3/Gal-9 pathway may play some important roles in early pregnancy and even embryo development.

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Section: Discussionsupporting

confidence: 92%

Galectin-9 Alleviates LPS-Induced Preeclampsia-Like Impairment in Rats via Switching Decidual Macrophage Polarization to M2 Subtype

Wang

Luan

et al. 2019

Front. Immunol.

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“…However, these subtle biochemical, synaptic, and ultrastructural differences may underlie the altered response to several physiological and pathological stimuli, like altered cortical axonal branching, changes in myelination process, inner ear structure, and cerebellar migration in the nervous system (Allais et al 2007;Tamas et al 2012;Vincze et al 2011;Yamada et al 2010). PACAP KO mice display several metabolic, behavioral, and inflammatory alterations (Abad and Tan 2018;Gaszner et al 2012;Hashimoto et al 2010;Hatanaka et al 2008;Lajko et al 2017;Maasz et al 2014;Sandor et al 2010) and have even altered intestinal bacterial flora (Heimesaat et al 2017). Differences are especially apparent under pathological circumstances, when PACAP-deficient mice show increased sensitivity to various stressors.…”

Section: Pacap Has Neuro-and General Cytoprotective Effectsmentioning

confidence: 99%

PACAP deficiency as a model of aging

et al. 2018

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Dysregulation of neuropeptides may play an important role in aging-induced impairments. In the long list of neuropeptides, pituitary adenylate cyclaseactivating polypeptide (PACAP) represents a highly effective cytoprotective peptide that provides an endogenous control against a variety of tissue-damaging stimuli. PACAP has neuro-and general cytoprotective effects due to anti-apoptotic, anti-inflammatory, and antioxidant actions. As PACAP is also a part of the endogenous protective machinery, it can be hypothesized that the decreased protective effects in lack of endogenous PACAP would accelerate age-related degeneration and PACAP knockout mice would display age-related degenerative signs earlier. Recent results support this hypothesis showing that PACAP deficiency mimics aspects of age-related pathophysiological changes including increased neuronal vulnerability and systemic degeneration accompanied by increased apoptosis, oxida-tive stress, and inflammation. Decrease in PACAP expression has been shown in different species from invertebrates to humans. PACAP-deficient mice display numerous pathological alterations mimicking early aging, such as retinal changes, corneal keratinization and blurring, and systemic amyloidosis. In the present review, we summarize these findings and propose that PACAP deficiency could be a good model of premature aging.

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“…Interestingly, in spite of PACAP deficient mice displaying disturbed spermatogenesis and altered testicular immunity (100,210), they also show delayed testicular aging supposedly due to the stimulatory effect of PACAP on testosterone production, which, in turn, accelerates aging due to increased oxidative stress (211). The involvement of PACAP has been described in numerous reproductive processes from fertilization to implantation (212)(213)(214). However, its direct cytoprotective effects have only been shown in a few cases.…”

Section: Reproductive Organsmentioning

confidence: 99%

Protective Effects of PACAP in Peripheral Organs

et al. 2020

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Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide widely distributed in the nervous system, where it exerts strong neuroprotective effects. PACAP is also expressed in peripheral organs but its peripheral protective effects have not been summarized so far. Therefore, the aim of the present paper is to review the existing literature regarding the cytoprotective effects of PACAP in non-neuronal cell types, peripheral tissues, and organs. Among others, PACAP has widespread expression in the digestive system, where it shows protective effects in various intestinal pathologies, such as duodenal ulcer, small bowel ischemia, and intestinal inflammation. PACAP is present in both the exocrine and endocrine pancreas as well as liver where it reduces inflammation and steatosis by interfering with hepatic pathology related to obesity. It is found in several exocrine glands and also in urinary organs, where, with its protective effects being mainly published regarding renal pathologies, PACAP is protective in numerous conditions. PACAP displays anti-inflammatory effects in upper and lower airways of the respiratory system. In the skin, it is involved in the development of inflammatory pathology such as psoriasis and also has anti-allergic effects in a model of contact dermatitis. In the non-neuronal part of the visual system, PACAP showed protective effects in pathological conditions of the cornea and retinal pigment epithelial cells. The positive role of PACAP has been demonstrated on the formation and healing processes of cartilage and bone where it also prevents osteoarthritis and rheumatoid arthritis development. The protective role of PACAP was also demonstrated in the cardiovascular system in different pathological processes including hyperglycaemia-induced endothelial dysfunction and age-related vascular changes. In the heart, PACAP protects against ischemia, oxidative stress, and cardiomyopathies. PACAP is also involved in the protection against the development of pre-senile systemic amyloidosis, which is presented in various peripheral organs in PACAP-deficient mice. The studies summarized here provide strong evidence for the cytoprotective effects of the peptide. The survival-promoting effects of PACAP depend on a number of factors which are also shortly discussed in the present review.

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Comparative analysis of decidual and peripheral immune cells and immune‐checkpoint molecules during pregnancy in wild‐type and PACAP‐deficient mice

Abstract: The only remarkable finding is the recruitment of Gal-9+ Th cells to the decidua promoting local immune homeostasis in PACAP KO mice, which nevertheless cannot explain the reduced fertility observed in these mice.

Cited by 13 publications

References 38 publications

Galectin-9 Alleviates LPS-Induced Preeclampsia-Like Impairment in Rats via Switching Decidual Macrophage Polarization to M2 Subtype

Galectin-9 Alleviates LPS-Induced Preeclampsia-Like Impairment in Rats via Switching Decidual Macrophage Polarization to M2 Subtype

PACAP deficiency as a model of aging

Protective Effects of PACAP in Peripheral Organs

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