Macrophage roles in the clearance of apoptotic cells and control of inflammation in the prostate gland after castration

Silva, Juliete A.F.; Bruni‐Cardoso, Alexandre; Augusto, Taize Machado; Damas-Souza, Danilo Marchete; Barbosa, Guilherme Oliveira; Felisbino, Sérgio Luís; Stach-Machado, Dagmar Ruth; Carvalho, Hernandes F.

doi:10.1002/pros.23449

Cited by 19 publications

(20 citation statements)

References 47 publications

(66 reference statements)

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“…Using the cytochemical technique of Gömöri's reticulin, it was possible to observe a disorder in the stromal compartments in the prostate of the EEA group, such as disorganization of the reticular and collagen fibers. The stromal remodeling may have been caused by an increased recruitment of macrophages, especially in the stroma, where this cell type can secrete different chemical and enzymatic mediators, actively participating in tissue remodeling (Silva et al, 2018), such as extracellular matrix metalloproteinases of types 2 and 9, as observed in prostate cancer in mice (Fang et al, 2013), in altered prostate tissue of male and female gerbils (Rochel‐Maia et al, 2011) and tissue remodeling in models with hydroxyapatite grafting, or in periodontal lesions (Carneiro et al, 2009; Zambuzzi et al, 2009). According to Falleiros‐Junior et al (2016), exposure to EE during the neonatal period promotes an increase in morphological alterations, such as foci of epithelial hyperplasia associated with inflammations in the stromal and luminal compartments of the ventral prostate of adult gerbils.…”

Section: Discussionmentioning

confidence: 99%

Ethinylestradiol and its effects on the macrophages in the prostate of adult and senile gerbils

Castro

Falleiros‐Júnior

Zucão

et al. 2020

Cell Biology International

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Prenatal and neonatal exposure to estrogenic compounds, such as ethinylestradiol (EE), promotes a variety of developmental disorders, including malformations and alterations in the morphology of glands, such as the prostate gland. Therefore, the aim of this study was to evaluate the morphological effects of neonatal exposure to EE on prostatic tissue and on the identification and quantification of gerbil gland macrophages in adult and senile Mongolian gerbils. The animals were exposed to EE (10 μg/kg/day) and to the vehicle, mineral oil (100 μL) (control group) during the first 10 days of postnatal life (lactation period). Adult gerbils were euthanized at 120 days and senile gerbils at 12 months of age. Our findings permitted verification of the presence of areas with proliferative foci in the prostate glandular portions in the adult and senile animals exposed to EE. There was also an increase in macrophages in the prostate tissue of adult and senile gerbils; these cell types alter the stromal microenvironment and possibly modify the interactions between the epithelium and stroma. Neonatal exposure to EE changes the pattern of prostatic development, leading to alterations in the arrangement of cells, including macrophages, and may be related to the onset of proliferative disorders in the prostate of adult gerbils and during aging.

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Section: Discussionmentioning

confidence: 99%

Ethinylestradiol and its effects on the macrophages in the prostate of adult and senile gerbils

Castro

Falleiros‐Júnior

Zucão

et al. 2020

Cell Biology International

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“…In order to investigate the occurrence of intraepithelial macrophages in the rat prostates, tissues sectioned at 4.0 µm were submitted to immunohistochemistry for CD68, a pan‐macrophage marker 22 . Additionally, to characterize the epithelial cells in close proximity to macrophages, immunostaining to detect cellular proliferation (MCM7) and apoptosis (cleaved caspase‐3) was also performed.…”

Section: Methodsmentioning

confidence: 99%

“…Macrophages have also been shown to interact with epithelial cells in a rather complex manner, 5 secreting factors that promote mutagenic events, cellular proliferation and motility 16‐18 . In the prostate, aside from the presence of stromal and perivascular macrophages, these cells have long been reported within the epithelium after androgen withdraw induced by castration 19‐23 . These intraepithelial macrophages appear to phagocytize apoptotic epithelial cells (efferocytosis) and contribute to the remodeling of the regressing prostate 19,22 .…”

Section: Introductionmentioning

confidence: 99%

“…In the prostate, aside from the presence of stromal and perivascular macrophages, these cells have long been reported within the epithelium after androgen withdraw induced by castration 19‐23 . These intraepithelial macrophages appear to phagocytize apoptotic epithelial cells (efferocytosis) and contribute to the remodeling of the regressing prostate 19,22 . Nevertheless, the presence of macrophages within the prostate epithelium has often been overlooked with regard to the pathological context.…”

Section: Introductionmentioning

confidence: 99%

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Tumor‐Associated Macrophages (TAM) are recruited to the aging prostate epithelial lesions and become intermingled with basal cells

et al. 2020

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Background Prostate cancer remains one of the most common cancers in men. Macrophages are thought to be important regulators in cancers, and their potential involvement in prostate cancer should not be overlooked. Therefore, the association between macrophages and the pre‐tumorous changes in prostate epithelium during aging deserves further investigation. Objectives We sought to investigate whether macrophages would be recruited into the prostate epithelium that display pathological lesions commonly found during aging. Materials and methods Prostates of aging rats, with and without treatment with a combination of testosterone and estradiol, were examined for premalignant and malignant epithelial lesions. For comparison, prostates of castrated rats were also investigated. Results Intraepithelial macrophages were found restricted to areas of premalignant and malignant lesions. An unprecedented interaction between macrophages and basal cells was observed in the aging pathological lesions. The intraepithelial macrophages were associated with autophagy, in contrast to those found after castration. In prostate lesions, the intraepithelial macrophages had TAM phenotype (CD68+/iNOS+/CD206+/ARG+), denoting a possible involvement in cancer progression. However, M2 macrophages (CD68+/CD163+) were recruited into the epithelium after castration, possibly to phagocytize cells undergoing apoptosis. Discussion and conclusion In conclusion, macrophages were recruited into the prostate epithelium and presented diverse phenotypes and morphology, consistent with changes reflected in the hormonal environment. Macrophages with the TAM phenotype were found restricted to areas of premalignant and malignant lesions in aging prostates, denoting a possible involvement in cancer progression. In contrast, M2 macrophages were found in the regressed epithelium after castration.

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“…For instance, remarkable reprogramming of immune system cells (Desai et al, 2004) and smooth muscle cells (Antonioli et al, 2004(Antonioli et al, , 2007 as well as reorganization of the extracellular matrix (Vilamaior et al, 2000) have been described and associated with a redefined functional state and immune barrier system. Additionally, we have reported the occurrence of desquamation as an additional phenomenon contributing to epithelial cell deletion (Rosa-Ribeiro et al, 2014a), and a relevant role for two macrophage subpopulations in both (a) the induction of epithelial cell death (Barbosa et al, 2019) and (b) the clearance of cell corpses and maintenance of the noninflammatory status (Silva et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulators and regulatory pathways involved in prostate gland adaptation to a hypoandrogen environment

et al. 2019

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Anti-androgen therapies, including orchiectomy, are effective at promoting prostate cancer remission, but are followed by progression to the more aggressive castration-resistant prostate cancer (CRPC). Castration promotes gland and tumor shrinkage. However, prostate adaptation to androgen deprivation involves striking parallel events, all requiring changes in gene expression. We hypothesized that transcription factors (TF) and other transcription-related genes are needed to orchestrate those changes. In this work, downstream analysis using bioinformatic tools and published microarray data allowed us to identify sixty transcriptional regulators (including 10 TF) and to integrate their function in physiologically relevant networks. Functional associations revealed a connection between Arnt, Bhlhe41 and Dbp circadian rhythm genes with the Ar circuitry and a small gene network centered in Pex14, which might indicate a previously unanticipated metabolic shift. We have also identified human homologs and mapped the corresponding genes to human chromosome regions commonly affected in prostate cancer, with particular attention to the PTEN/HHEX/MXI1 cluster at 10q23-25 (frequently deleted in PCa) and to MAPK1 at 22q11.21 (delete in intermediate risk but not in high risk PCa). Twenty genes were found mutated or with copy number alterations in at least five percent of three cancer cohorts and six of them (PHOX2A, NFYC, EST2, EIF2S1, SSRP1 and PARP1) associated with impacted patient survival. These changes are specific to the adaptation to the hypoandrogen environment and seem important for the progression to CRPC when mutated.

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Macrophage roles in the clearance of apoptotic cells and control of inflammation in the prostate gland after castration

Abstract: CD68 macrophages phagocytose apoptotic cell corpses and activate the LAP pathway, thereby contributing to the preservation of a non-inflammed microenvironment. Marked inflammation was detected when autophagy blockers were administered to castrated animals.

Cited by 19 publications

References 47 publications

Ethinylestradiol and its effects on the macrophages in the prostate of adult and senile gerbils

Ethinylestradiol and its effects on the macrophages in the prostate of adult and senile gerbils

Tumor‐Associated Macrophages (TAM) are recruited to the aging prostate epithelial lesions and become intermingled with basal cells

Transcriptional regulators and regulatory pathways involved in prostate gland adaptation to a hypoandrogen environment

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