Abstract
SummaryDelayed-type hypersensitivity (DTH) responses underpin chronic inflammation. Using a model of oxazolone-induced dermatitis and a combination of transgenic mice, adoptive cell transfer, and selective agonists/antagonists against protease activated receptors, we show that that PAR-1 signaling on macrophages by thrombin is required for effective granuloma formation. Using BM-derived macrophages (BMMs) in vitro, we show that thrombin signaling induced (a) downregulation of cell membrane reverse cholesterol transporter ABCA1 and (b) increased expression of IFNγ receptor and enhanced co-localization within increased areas of cholesterol-rich membrane microdomains. These two key phenotypic changes combined to make thrombin-primed BMMs sensitive to M1 polarization by 1000-fold less IFNγ, compared to resting BMMs. We confirm that changes in ABCA1 expression were directly responsible for the exquisite sensitivity to IFNγ in vitro and for the impact on granuloma formation in vivo. These data indicate that PAR-1 signaling plays a hitherto unrecognized and critical role in DTH responses.
Highlights
Macrophages are heterogeneous and versatile cells found in virtually all tissues of adult mammals
Using a model of oxazolone-induced dermatitis and a combination of transgenic mice, adoptive cell transfer, and selective agonists/antagonists against protease activated receptors, we show that that PAR-1 signaling on macrophages by thrombin is required for effective granuloma formation
Using bone marrow (BM)-derived macrophages (BMMs) in vitro, we show that thrombin signaling induced (a) downregulation of cell membrane reverse cholesterol transporter ATP-binding cassette transporter 1 (ABCA1) and (b) increased expression of IFNg receptor and enhanced co-localization within increased areas of cholesterol-rich membrane microdomains
Summary
Macrophages are heterogeneous and versatile cells found in virtually all tissues of adult mammals. Literature described them dichotomously as M1 or M2 macrophages (Mills, 2015), with M1 macrophages being the classical inflammatory macrophages induced by T-cell-dependent (interferon g [IFNg]) and T-cell-independent (lipopolysaccharide [LPS]) pathways These promote upregulation of Th1 proinflammatory chemokines and cytokines such as IL-6, IL-12, and IL-23. Subsets with a predominant M2 phenotype (M2a-d) have been defined, having anti-inflammatory roles in the Th2 response (M2a), suppression of tumor growth (M2b), immune regulation and tissue remodeling (M2c), and angiogenesis (M2d). These M2 subsets have different polarizing stimuli, eg. What is becoming clear is the classical/alternative model of macrophage activation does not take into account the subtle changes occurring in the cell microenvironment which can have tangible changes to the cell phenotype without fully polarizing the cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
