Hepatic mast cell concentration directly correlates to stage of fibrosis in NASH

Lombardo, Jamie; Broadwater, Devin R.; Collins, Ryan; Cebe, Katherine; Brady, Robert; Harrison, Stephen A.

doi:10.1016/j.humpath.2018.11.029

Cited by 24 publications

(23 citation statements)

References 13 publications

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“…In liver fibrosis, macrophages play a role in both the injury and the recovery process (Duffield et al, 2005), while a depletion of macrophages in lung fibrosis has led to an amelioration of the disease (Misharin et al, 2017). A positive correlation between the number of mast cells present in liver and lung tissue and the severity of fibrosis in these organs have been described (Pesci et al, 1993;Lombardo et al, 2019). These data suggest that macrophages and mast cells may play a role in the initiation of testicular fibrosis in KS, starting at adolescence.…”

Section: Discussionmentioning

confidence: 93%

“…In non-KS azoospermic men, an increase in macrophage and mast cell number has been reported (Meineke et al, 2000;Apa et al, 2002;Frungieri et al, 2002;Roaiah et al, 2007). Previous studies showed an association between these immune cells and liver and pulmonary fibrosis, suggesting a possible role for macrophages and mast cells in the KS testicular fibrosis (Pesci et al, 1993;Duffield et al, 2005;Misharin et al, 2017;Lombardo et al, 2019). The secretory products of macrophages and mast cells, tumour necrosis factor alpha (TNF-a) and tryptase, respectively, have already been associated with the peritubular myoid cells (PTMC), which surround the seminiferous tubules.…”

Section: Introductionmentioning

confidence: 94%

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Testicular immune cells and vasculature in Klinefelter syndrome from childhood up to adulthood

et al. 2020

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Abstract STUDY QUESTION Is the distribution of immune cells and the testicular vasculature altered in testicular biopsies from patients with Klinefelter syndrome (KS)? SUMMARY ANSWER Increased numbers of macrophages and mast cells, an increased expression of decorin and an increased blood vessel density were found in KS samples compared to controls. WHAT IS KNOWN ALREADY Most KS patients are infertile due to an early germ cell loss. From puberty onwards, testicular fibrosis can be detected. How this fibrotic process is initiated remains unknown. STUDY DESIGN, SIZE, DURATION In this study, the number of macrophages, mast cells and their secretory products were evaluated in KS, Sertoli cell only (SCO) and control patient samples. The association between immune cell numbers and level of fibrosis in KS tissue was examined. In addition, the vascularization within these testicular tissue biopsies was studied. For immunohistochemical evaluation, KS patients at different stages of testicular development were included: prepubertal (aged 4–7 years; n = 4), peripubertal (aged 11–17 years; n = 21) and adult (aged >18 years; n = 37) patients. In addition, testicular tissue biopsies of adult SCO (n = 33) and control samples for the three KS age groups (prepubertal n = 9; peripubertal n = 5; adult n = 25) were analysed. Gene expression analysis was performed on adult testicular tissue from KS (n = 5), SCO (n = 5) and control (n = 5) patients. PARTICIPANTS/MATERIALS, SETTING, METHODS Adult (>18 years) KS, SCO and control testicular tissue biopsies were obtained during a testicular sperm extraction procedure. KS peripubertal (11–18 years), prepubertal (<11 years) and age-matched control biopsies were obtained from the biobank of the university hospital. Immunohistochemistry was used to determine the tubular structure (H/PAS), the number of spermatogonia (MAGE-A4), macrophages (CD68) and mast cells (tryptase) and the blood vessel density (Von Willebrand factor). In addition, quantitative real-time polymerase chain reaction was used to determine the expression of secretory products of macrophages and mast cells (tryptase, tumour necrosis factor alpha and decorin). MAIN RESULTS AND THE ROLE OF CHANCE A significant increase in the number of macrophages (P < 0.0001) and mast cells (P = 0.0008) was found in the peritubular compartment of testes of adult KS patients compared to control samples. However, no association between the number of immune cells and the degree of fibrosis was observed. In adult SCO samples, a significant increase was seen for peritubular macrophage (P < 0.0001) and mast cell (P < 0.0001) numbers compared to control samples. In the interstitial compartment, a significant increase in mast cell number was found in adult SCO samples compared to KS (P < 0.0001) and control (P < 0.0001) tissue. A significant difference (P = 0.0431) in decorin expression could be detected in adult KS compared to control patients. Decorin expression was mostly seen in the walls of the seminiferous tubules. When comparing the vascularization between KS patients and age-matched controls, a significant increase (P = 0.0081) in blood vessel density could be observed only in prepubertal KS testicular tissue. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION As controls for this study, testicular tissue biopsies of men who underwent a vasectomy reversal or orchiectomy were used, but these men may not represent fertile controls. In addition, a high variability in immune cell numbers, secretory products expression and number of blood vessels could be observed amongst all patient samples. WIDER IMPLICATIONS OF THE FINDINGS Increased numbers of macrophages and mast cells have previously been described in non-KS infertile men. Our results show that these increased numbers can also be detected in KS testicular tissue. However, no association between the number of macrophages or mast cells and the degree of fibrosis in KS samples could be detected. Decorin has previously been described in relation to fibrosis, but it has not yet been associated with testicular fibrosis in KS. Our results suggest a role for this proteoglycan in the fibrotic process since an increased expression was observed in adult KS tissue compared to controls. Impaired vascularization in KS men was suggested to be responsible for the KS-related disturbed hormone levels. Our results show a significant difference in blood vessel density, especially for the smallest blood vessels, between prepubertal KS samples and age-matched controls. This is the first study to report differences between KS and control testicular tissue at prepubertal age. STUDY FUNDING/COMPETING INTEREST(S) The project was funded by grants from the Vrije Universiteit Brussel (E.G.) and the scientific Fund Willy Gepts from the UZ Brussel (D.V.S.). D.V.S. is a post-doctoral fellow of the Fonds voor Wetenschappelijk Onderzoek (FWO; 12M2819N). No conflict of interest is declared for this research project.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 94%

Testicular immune cells and vasculature in Klinefelter syndrome from childhood up to adulthood

et al. 2020

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“…Mast cells are present in the liver; their numbers have been reported to increase in chronic liver diseases associated with fibrosis in human and experimental models [ 17 , 61 ]. Chymase has also been closely associated with the progression of tissue fibrosis because it promotes the formation of TGF-β from the non-bioactive precursor TGF-β, and TGF-β strongly induces fibroblast growth [ 62 ].…”

Section: Experimental Evidences On Chymase Inhibitors In Nafld/nasmentioning

confidence: 99%

Chymase as a Possible Therapeutic Target for Amelioration of Non-Alcoholic Steatohepatitis

Jin

2020

IJMS

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The development and progression of non-alcoholic steatohepatitis (NASH) are linked to oxidative stress, inflammation, and fibrosis of the liver. Chymase, a chymotrypsin-like enzyme produced in mast cells, has various enzymatic actions. These actions include activation of angiotensin II, matrix metalloproteinase (MMP)-9, and transforming growth factor (TGF)-β, which are associated with oxidative stress, inflammation, and fibrosis, respectively. Augmentation of chymase activity in the liver has been reported in various NASH models. Generation of hepatic angiotensin II and related oxidative stress is upregulated in NASH but attenuated by treatment with a chymase inhibitor. Additionally, increases in MMP-9 and accumulation of inflammatory cells are observed in NASH but are decreased by chymase inhibitor administration. TGF-β and collagen I upregulation in NASH is also attenuated by chymase inhibition. These results in experimental NASH models demonstrate that a chymase inhibitor can effectively ameliorate NASH via the reduction of oxidative stress, inflammation, and fibrosis. Thus, chymase may be a therapeutic target for amelioration of NASH.

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“…Lastly, mast cells are also derived from hematopoietic cells and have been implicated to regulate the pathogenesis of NAFLD. 38 – 40 Considering this, it would be interesting to explore whether Pfkfb3 also regulates the function of mast cells, thereby altering the development of hepatic steatosis and inflammation in future studies. Although not belonging to hematopoietic cells, hepatic stellate cells (HSCs) respond to macrophage-derived factors and are responsible for liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Adoptive transfer of Pfkfb3-disrupted hematopoietic cells to wild-type mice exacerbates diet-induced hepatic steatosis and inflammation

Guo

Zhu

et al. 2020

Liver Research

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Background and objectives: Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease (NAFLD). However, whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated. Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 ( Pfkfb3/ iPfk2) dissociates fat deposition and inflammation, the present study examined a role for Pfkfb3/ iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice. Methods: Pfkfb3 -disrupted ( Pfkfb3 +/−) mice and wild-type (WT) littermates were fed a high-fat diet (HFD) and examined for NAFLD phenotype. Also, bone marrow cells isolated from Pfkfb3 +/− mice and WT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation (BMT) to generate chimeric (WT/BMT- Pfkfb3 +/−) mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric (WT/BMT-WT) mice. The latter were also fed an HFD and examined for NAFLD phenotype. In vitro , hepatocytes were co-cultured with bone marrow-derived macrophages and examined for hepatocyte fat deposition and proinflammatory responses. Results: After the feeding period, HFD-fed Pfkfb3 +/− mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice. When inflammatory activation was analyzed, Pfkfb3 +/− macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation. When NAFLD phenotype was analyzed in the chimeric mice, WT/BMT- Pfkfb3 +/− mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice. At the cellular level, hepatocytes co-cultured with Pfkfb3 +/− macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages. Conclusions: Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/ iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis. As such, the Pfkfb3/ iPfk2 plays a unique role in regulating NAFLD pathophysiology.

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Hepatic mast cell concentration directly correlates to stage of fibrosis in NASH

Cited by 24 publications

References 13 publications

Testicular immune cells and vasculature in Klinefelter syndrome from childhood up to adulthood

Testicular immune cells and vasculature in Klinefelter syndrome from childhood up to adulthood

Chymase as a Possible Therapeutic Target for Amelioration of Non-Alcoholic Steatohepatitis

Adoptive transfer of Pfkfb3-disrupted hematopoietic cells to wild-type mice exacerbates diet-induced hepatic steatosis and inflammation

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