Microenvironmental signals govern the cellular identity of testicular macrophages

Meinhardt, Andreas; Wang, Ming; Schulz, Christian; Bhushan, Sudhanshu

doi:10.1002/jlb.3mr0318-086rr

Cited by 45 publications

(51 citation statements)

References 113 publications

(283 reference statements)

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“…In both rodents and humans, macrophages represent the largest population of immune cells in the testis and play a key role in maintaining testis immune privilege (457,485). Rodent and primate testis macrophages display an M2-like phenotype.…”

Section: The Role Of Resident Immune Cells In the Immune Privilege Ofmentioning

confidence: 99%

“…In response to infection or inflammatory stimuli, rodent testis macrophages exhibit relatively low inflammatory responses and high immunosuppressive properties compared with macrophages located in others tissues (reviewed in (457)), which confer upon them a unique immune-tolerant role against meiotic germ cells antigens that egress from seminiferous tubules. Blocked NF-kB signaling pathway and basal corticosterone production in rat testicular macrophages is associated with reduced pro-inflammatory capacities (457). In the mouse, interstitial embryo-derived macrophages have more potent immune suppressive properties than peritubular macrophages, which are derived from the bone marrow after birth (484).…”

Section: The Role Of Resident Immune Cells In the Immune Privilege Ofmentioning

confidence: 99%

See 1 more Smart Citation

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

Tortorec

Matusali

Mahé

et al. 2020

Physiological Reviews

103

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The male genital tract (MGT) is the target of a number of viral infections that can have deleterious consequences at the individual, offspring, and population levels. These consequences include infertility, cancers of male organs, transmission to the embryo/fetal development abnormalities, and sexual dissemination of major viral pathogens such as human immunodeficiency virus (HIV) and hepatitis B virus. Lately, two emerging viruses, Zika and Ebola, have additionally revealed that the human MGT can constitute a reservoir for viruses cleared from peripheral circulation by the immune system, leading to their sexual transmission by cured men. This represents a concern for future epidemics and further underlines the need for a better understanding of the interplay between viruses and the MGT. We review here how viruses, from ancient viruses that integrated the germline during evolution through old viruses (e.g., papillomaviruses originating from Neanderthals) and more modern sexually transmitted infections (e.g., simian zoonotic HIV) to emerging viruses (e.g., Ebola and Zika) take advantage of genital tract colonization for horizontal dissemination, viral persistence, vertical transmission, and endogenization. The MGT immune responses to viruses and the impact of these infections are discussed. We summarize the latest data regarding the sources of viruses in semen and the complex role of this body fluid in sexual transmission. Finally, we introduce key animal findings that are relevant for our understanding of viral infection and persistence in the human MGT and suggest future research directions.

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Section: The Role Of Resident Immune Cells In the Immune Privilege Ofmentioning

confidence: 99%

Section: The Role Of Resident Immune Cells In the Immune Privilege Ofmentioning

confidence: 99%

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

Tortorec

Matusali

Mahé

et al. 2020

Physiological Reviews

103

View full text Add to dashboard Cite

show abstract

“…For instance, reliance on mir-511-3p targeting does not allow for precise differentiation between M2 macrophages and moDCs, or the relative contribution of both cell types in ZIKV infection of the testicular interstitium. Macrophages (M2 macrophages in particular) are the most abundant leukocyte population in the mammalian testes [27,66]. For primates, it was shown that M2 macrophages expressing CD169 marker are~200 times more abundant compared to all subtypes of testicular DCs [23].…”

Section: Plos Pathogensmentioning

confidence: 99%

“…It was recently shown that primary human Leydig cells fail to support efficient ZIKV replication in cell culture [25,26]. In contrast, studies of IFN-receptor deficient mice and human testicular explants demonstrated that ZIKV can infect macrophages, which constitute the most abundant group of testicular leukocytes [23,27], rather than myoid or Leydig cells [19,28]. These studies suggest that testicular macrophages may be the primary target for early ZIKV infection in the testicular interstitium.…”

Section: Introductionmentioning

confidence: 99%

Zika virus tropism during early infection of the testicular interstitium and its role in viral pathogenesis in the testes

et al. 2020

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Sexual transmission and persistence of Zika virus (ZIKV) in the testes pose new challenges for controlling virus outbreaks and developing live-attenuated vaccines. It has been shown that testicular infection of ZIKV is initiated in the testicular interstitium, followed by spread of the virus in the seminiferous tubules. This leads to testicular damage and/or viral dissemination into the epididymis and eventually into semen. However, it remains unknown which cell types are targeted by ZIKV in the testicular interstitium, and what is the specific order of infectious events leading to ZIKV invasion of the seminiferous tubules. Here, we demonstrate that interstitial leukocytes expressing mir-511-3p microRNA are the initial targets of ZIKV in the testes, and infection of mir-511-3p-expressing cells in the testicular interstitium is necessary for downstream infection of the seminiferous tubules. Mir-511-3p is expressed concurrently with CD206, a marker of lineage 2 (M2) macrophages and monocyte derived dendritic cells (moDCs). Selective restriction of ZIKV infection of CD206-expressing M2 macrophages/moDCs results in the attenuation of macrophage-associated inflammatory responses in vivo and prevents the disruption of the Sertoli cell barrier in vitro. Finally, we show that targeting of viral genome for mir-511-3p significantly attenuates early ZIKV replication not only in the testes, but also in many peripheral organs, including spleen, epididymis, and pancreas. This incriminates M2 macrophages/moDCs as important targets for visceral ZIKV replication following hematogenous dissemination of the virus from the site of infection.

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“…However, they are characterized by a subdued proinflammatory response, a polarization toward the immunoregulatory and immunotolerant phenotype that enables them to play a relevant role in the functions of the testis. During infection, the characteristic blunted immune response of tissue macro-phages reflects the need for a delicate balance between a sufficiently strong reaction to counteract invading pathogens, and the prevention of excessive proinflammatory cytokine levels with the potential to disturb or destroy spermatogenesis (Meinhardt et al, 2018). The content of CD11b+ cells remained elevated over a period of observation.…”

Section: Discussionmentioning

confidence: 99%

Selenoproteins and their emerging roles in signaling pathways

Stanishevska

2020

Regul. Mech. Biosyst.

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The functional activity of selenoproteins has a wide range of effects on complex pathogenetic processes, including teratogenesis, immuno-inflammatory, neurodegenerative. Being active participants and promoters of many signaling pathways, selenoproteins support the lively interest of a wide scientific community. This review is devoted to the analysis of recent data describing the participation of selenoproteins in various molecular interactions mediating important signaling pathways. Data processing was carried out by the method of complex analysis. For convenience, all selenoproteins were divided into groups depending on their location and function. Among the group of selenoproteins of the ER membrane, selenoprotein N affects the absorption of Ca2+ by the endoplasmic reticulum mediated by oxidoreductin (ERO1), a key player in the CHOP/ERO1 branch, a pathogenic mechanism that causes myopathy. Another selenoprotein of the ER membrane selenoprotein K binding to the DHHC6 protein affects the IP3R receptor that regulates Ca2+ flux. Selenoprotein K is able to affect another protein of the endoplasmic reticulum CHERP, also appearing in Ca2+ transport. Selenoprotein S, associated with the lumen of ER, is able to influence the VCP protein, which ensures the incorporation of selenoprotein K into the ER membrane. Selenoprotein M, as an ER lumen protein, affects the phosphorylation of STAT3 by leptin, which confirms that Sel M is a positive regulator of leptin signaling. Selenoprotein S also related to luminal selenoproteins ER is a modulator of the IRE1α-sXBP1 signaling pathway. Nuclear selenoprotein H will directly affect the suppressor of malignant tumours, p53 protein, the activation of which increases with Sel H deficiency. The same selenoprotein is involved in redox regulation. Among the cytoplasmic selenoproteins, abundant investigations are devoted to SelP, which affects the PI3K/Akt/Erk signaling pathway during ischemia/reperfusion, is transported into the myoblasts through the plasmalemma after binding to the apoER2 receptor, and into the neurons to the megaline receptor and in general, selenoprotein P plays the role of a pool that stores the necessary trace element and releases it, if necessary, for vital selenoproteins. The thioredoxin reductase family plays a key role in the invasion and metastasis of salivary adenoid cystic carcinoma through the influence on the TGF-β-Akt/GSK-3β pathway during epithelial-mesenchymal transition. The deletion of thioredoxin reductase 1 affects the levels of messengers of the Wnt/β-catenin signaling pathway. No less studied is the glutathione peroxidase group, of which GPX3 is able to inhibit signaling in the Wnt/β-catenin pathway and thereby inhibit thyroid metastasis, as well as suppress protein levels in the PI3K/Akt/c-fos pathway. A key observation is that in cases of carcinogenesis, a decrease in GPX3 and its hypermethylation are almost always found. Among deiodinases, deiodinase 3 acts as a promoter of the oncogenes BRAF, MEK or p38, while stimulating a decrease in the expression of cyclin D1. The dependence of the level of deiodinase 3 on the Hedgehog (SHH) signaling pathway is also noted. Methionine sulfoxide reductase A can compete for the uptake of ubiquitin, reduce p38, JNK and ERK promoters of the MAPK signaling pathway; methionine sulfoxide reductase B1 suppresses MAPK signaling messengers, and also increases PARP and caspase 3.

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Microenvironmental signals govern the cellular identity of testicular macrophages

Cited by 45 publications

References 113 publications

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

Zika virus tropism during early infection of the testicular interstitium and its role in viral pathogenesis in the testes

Selenoproteins and their emerging roles in signaling pathways

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