Dataset Information

Solid-phase immunoglobulins IgG and IgM activate macrophages with solid-phase IgM acting via a novel scavenger receptor a pathway.

ABSTRACT: IgG may accelerate atherosclerosis via ligation of proinflammatory Fc? receptors; however, IgM is unable to ligate Fc?R and is often considered vasculoprotective. IgM aggravates ischemia-reperfusion injury, and solid-phase deposits of pure IgM, as seen with IgM-secreting neoplasms, are well known clinically to provoke vascular inflammation. We therefore examined the molecular mechanisms by which immunoglobulins can aggravate vascular inflammation, such as in atherosclerosis. We compared the ability of fluid- and solid-phase immunoglobulins to activate macrophages. Solid-phase immunoglobulins initiated prothrombotic and proinflammatory functions in human macrophages, including NF-?B p65 activation, H(2)O(2) secretion, macrophage-induced apoptosis, and tissue factor expression. Responses to solid-phase IgG (but not to IgM) were blocked by neutralizing antibodies to CD16 (Fc?RIII), consistent with its known role. Macrophages from mice deficient in macrophage scavenger receptor A (SR-A; CD204) had absent IgM binding and no activation by solid-phase IgM. RNA interference-mediated knockdown of SR-A in human macrophages suppressed activation by solid-phase IgM. IgM binding to SR-A was demonstrated by both co-immunoprecipitation studies and the binding of fluorescently labeled IgM to SR-A-transfected cells. Immunoglobulins on solid-phase particles around macrophages were found in human plaques, increased in ruptured plaques compared with stable ones. These observations indicate that solid-phase IgM and IgG can activate macrophages and destabilize vulnerable plaques. Solid-phase IgM activates macrophages via a novel SR-A pathway.

SUBMITTER: Boyle JJ

PROVIDER: S-EPMC5691330 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Solid-phase immunoglobulins IgG and IgM activate macrophages with solid-phase IgM acting via a novel scavenger receptor a pathway.

Boyle Joseph J JJ Christou Ivy I Iqbal M Bilal MB Nguyen Aivi T AT Leung Viola W Y VW Evans Paul C PC Liu Yu Y Johns Michael M Kirkham Paul P Haskard Dorian O DO

The American journal of pathology 20120530 1

IgG may accelerate atherosclerosis via ligation of proinflammatory Fcγ receptors; however, IgM is unable to ligate FcγR and is often considered vasculoprotective. IgM aggravates ischemia-reperfusion injury, and solid-phase deposits of pure IgM, as seen with IgM-secreting neoplasms, are well known clinically to provoke vascular inflammation. We therefore examined the molecular mechanisms by which immunoglobulins can aggravate vascular inflammation, such as in atherosclerosis. We compared the abil ...[more]

PMID: 22658487

Similar Datasets

Project description:Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of ?-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, ?-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of ?-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in enterocyte differentiation.

Project description:BackgroundA profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications of critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable of mitigating the inflicted inflammatory harm. However, the efficacy of intravenous IgM-enriched preparations in critically ill patients with COVID-19 is largely unclear.MethodsIn this retrospective multicentric cohort study, 316 patients with laboratory-confirmed critical COVID-19 were treated in ten German and Austrian ICUs between May 2020 and April 2021. The primary outcome was 30-day mortality. Analysis was performed by Cox regression models. Covariate adjustment was performed by propensity score weighting using machine learning-based SuperLearner to overcome the selection bias due to missing randomization. In addition, a subgroup analysis focusing on different treatment regimens and patient characteristics was performed.ResultsOf the 316 ICU patients, 146 received IgM-enriched immunoglobulins and 170 cases did not, which served as controls. There was no survival difference between the two groups in terms of mortality at 30 days in the overall cohort (HRadj: 0.83; 95% CI: 0.55 to 1.25; p = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance (HRadj: 0.23; 95% CI: 0.05 to 1.08; p = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of ≥ 15 g and a duration of ≥ 3 days of IgM-enriched immunoglobulins were applied (HRadj: 0.65; 95% CI: 0.41 to 1.03; p = 0.068).ConclusionsAlthough we cannot prove a statistically reliable effect of intravenous IgM-enriched immunoglobulins, the confidence intervals may suggest a clinically relevant effect in certain subgroups. Here, an early administration (i.e. in critically ill but not yet mechanically ventilated COVID-19 patients) and a dose of ≥ 15 g for at least 3 days may confer beneficial effects without concerning safety issues. However, these findings need to be validated in upcoming randomized clinical trials. Trial registration DRKS00025794 , German Clinical Trials Register, https://www.drks.de . Registered 6 July 2021.

Dataset Information

Solid-phase immunoglobulins IgG and IgM activate macrophages with solid-phase IgM acting via a novel scavenger receptor a pathway.

Publications

Solid-phase immunoglobulins IgG and IgM activate macrophages with solid-phase IgM acting via a novel scavenger receptor a pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets