Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors including CD163 and CD206, ...which are upregulated in response to inflammation. In healthy individuals, soluble forms of CD163 and CD206 are constitutively shed from macrophages, however, during inflammation pathogen- and damage-associated stimuli induce this shedding. Activation of resident liver macrophages viz. Kupffer cells is part of the inflammatory cascade occurring in acute and chronic liver diseases. We here review the existing literature on sCD163 and sCD206 function and shedding, and potential as biomarkers in acute and chronic liver diseases with a particular focus on Acute-on-Chronic Liver Failure (ACLF). In multiple studies sCD163 and sCD206 are elevated in relation to liver disease severity and established as reliable predictors of morbidity and mortality. However, differences in expression- and shedding-stimuli for CD163 and CD206 may explain dissimilarities in prognostic utility in patients with acute decompensation of cirrhosis and ACLF.
The hemoglobin receptor CD163 and the mannose receptor CD206 are both expressed on the surface of human macrophages. Upon inflammatory activation, the receptors are shed from the macrophage surface ...generating soluble products. The plasma concentration of both soluble CD163 (sCD163) and soluble CD206 (sCD206) are increased in several diseases, including inflammatory conditions and cancer. Here, we show that in contrast to CD163, LPS-mediated shedding of CD206 in humans is slow and a result of indirect signaling. Although both sCD163 and sCD206 were increased in response to LPS stimulation in vivo, only CD163 was shed from LPS-stimulated macrophages in vitro. Although both sCD163 and sCD206 were released from cultured macrophages stimulated with zymosan and PMA, shedding of CD206 was generally slower and less efficient and not reduced by inhibitors against the major protease classes. These data indicate that CD163 and CD206 are shed from the macrophages by very different mechanisms potentially involving distinctive inflammatory processes.
Background: Extracellular vesicles (EVs) are implicated in intercellular communication in liver diseases. An EV-associated fraction of the macrophage biomarker soluble CD163, denoted EV-CD163, was ...recently identified. EV-CD163 may be released during later phases of the inflammatory response as opposed to the acute shedding of CD163 ectodomain (Ecto-CD163). Total sCD163 is a well-described biomarker in liver inflammation, and we investigated the distribution of CD163 fractions along with EV-associated soluble CD206 (EV-CD206) in patients with acute and chronic alcoholic liver inflammation.
Methods: Patients with acute alcoholic hepatitis (AH) (n = 48) and alcoholic cirrhosis (AC) (n = 26) were enrolled. Patients with AH were followed for 30 days after diagnosis. Healthy blood donors (n = 30) served as a reference group. Fractions of sCD163 and sCD206 were separated using ExoQuick™ and measured by ELISA.
Results: We demonstrated a possible EV-associated fraction of CD206 in plasma, correlating with levels of EV-CD163 (r
s
= 0.46, p < .001). The distribution of biomarker fractions was skewed toward EVs in chronic cirrhosis for both biomarkers (median: 35.8% EV-CD163, 58.8% EV-CD206) as compared to AH patients (median: 26.2% EV-CD163 p < .0001, 48.8% EV-CD206, p < .01). In AH patients, total sCD163 and Ecto-CD163 at inclusion were related to survival, whereas EV-CD163 was not.
Conclusion: Extracellular vesicles of macrophage origin associated with membrane receptors CD163 and CD206 are present in liver disease. We observed a shift in the distribution towards an increased EV fraction in chronic liver cirrhosis. These data support that Ecto and EV fractions may be markers of different inflammatory processes, possibly resulting from a switch in macrophage phenotype.
The macrophage activation marker soluble (s)CD163 is associated with disease severity and prognosis in patients with primary biliary cholangitis (PBC). Ursodeoxycholic acid (UDCA) treatment ...attenuates fibrosis progression in PBC patients, but its effect on macrophage activation is unclear. We examined the effect of UDCA on macrophage activation, as determined by sCD163 levels.
We included 2 cohorts of PBC patients; 1 cohort with prevalent PBC patients, and 1 cohort of incident PBC patients before start of UDCA treatment and with follow-up after 4 weeks and 6 months. We measured sCD163 and liver stiffness in both cohorts. Further, we measured sCD163 and TNF-α shedding in vitro in monocyte-derived macrophages after UDCA and lipopolysaccharide incubation.
We included 100 patients with prevalent PBC 93% women, median age 63 y (interquartile range: 51-70) and 47 patients with incident PBC 77% women, median age 60 y (49-67). Prevalent PBC patients had a lower median sCD163 of 3.54 mg/L (2.77-4.72) than incident PBC patients with a median sCD163 of 4.33 mg/L (2.83-5.99) at inclusion. Patients with an incomplete response to UDCA and patients with cirrhosis had higher sCD163 than responders to UDCA and noncirrhosis patients. After 4 weeks and 6 months of UDCA treatment median sCD163 decreased by 4.6% and 9.0%, respectively. In in vitro experiments, UDCA attenuated shedding of TNF-α, but not sCD163, from monocyte-derived macrophages.
In PBC patients, sCD163 levels correlated with liver disease severity and treatment response to UDCA. Further, after 6 months of UDCA treatment, we observed a decrease in sCD163, which may be related to the treatment.
Microarray and RT-PCR based methods are important tools for analysis of gene expression; however, in tissues containing many different cells types, such as the testis, characterization of gene ...expression in specific cell types can be severely hampered by noise from other cells. The laser microdissection technology allows for enrichment of specific cell types. However, when the cells are not morphologically distinguishable, it is necessary to use a specific staining method for the target cells. In this study we have tested different fixatives, storage conditions for frozen sections and staining protocols, and present two staining protocols for frozen sections, one for fast and specific staining of fetal germ cells, testicular carcinoma in situ cells, and other cells with embryonic stem cell-like properties that express the alkaline phosphatase, and one for specific staining of lipid droplet-containing cells, which is useful for isolation of the androgen-producing Leydig cells. Both protocols retain a morphology that is compatible with laser microdissection and yield RNA of a quality suitable for PCR and microarray analysis.
Abstract
Background
Although mother-to-child human immunodeficiency virus (HIV) transmission has dramatically decreased with maternal antiretroviral therapy, breast milk transmission accounts for ...most of the 180 000 new infant HIV infections annually. Broadly neutralizing antibodies (bNAb) may further reduce transmission.
Methods
A Phase 1 safety and pharmacokinetic study was conducted: a single subcutaneous (SC) dose of 20 or 40 mg/kg (Dose Groups 1 and 2, respectively) of the bNAb VRC01 was administered to HIV-exposed infants soon after birth. Breastfeeding infants (Dose Group 3) received 40 mg/kg SC VRC01 after birth and then 20 mg/kg/dose SC monthly. All infants received appropriate antiretroviral prophylaxis.
Results
Forty infants were enrolled (21 in the United States, 19 in Africa). Subcutaneous VRC01 was safe and well tolerated with only mild-to-moderate local reactions, primarily erythema, which rapidly resolved. For multiple-dose infants, local reactions decreased with subsequent injections. VRC01 was rapidly absorbed after administration, with peak concentrations 1–6 days postdose. The 40 mg/kg dose resulted in 13 of 14 infants achieving the serum 50 micrograms (mcg)/mL target at day 28. Dose Group 3 infants maintained concentrations greater than 50 mcg/mL throughout breastfeeding.
Conclusions
Subcutaneous VRC01 as single or multiple doses is safe and well tolerated in very young infants and is suitable for further study to prevent HIV transmission in infants.
Safety and pharmacokinetics of VRC01, a broadly neutralizing monoclonal antibody, was evaluated in HIV-exposed neonates. VRC01 was well tolerated with frequent mild local reactions. Birth dose of 40 mg/kg and monthly dose of 20 mg/kg achieved target trough serum levels.
This is a call for action to scientific journals to introduce reporting requirements for toxicity and ecotoxicity studies. Such reporting requirements will support the use of peer‐reviewed research ...studies in regulatory decision‐making. Moreover, this could improve the reliability and reproducibility of published studies in general and make better use of the resources spent in research.
This is a call for action to scientific journals to introduce reporting requirements for toxicity and ecotoxicity studies. Such reporting requirements will support the use of peer‐reviewed research studies in regulatory decision‐making. Moreover, this could improve the reliability and reproducibility of published studies in general and make better use of the resources spent in research.
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