Regulation of macrophage polarization and plasticity by complex activation signals. Issue 9 (5th August 2016)

• Record Type: Journal Article
• Authors: Smith, Tim D.; Tse, Margaret J.; Read, Elizabeth L.; Liu, Wendy F.
• Is Part Of: Integrative biology. Volume 8:Issue 9(2016:Sep.)
• Page Start: 946
• Page End: 955
• Publication Date: 2016-08-05
• Subjects: Biology -- Periodicals; Technology -- Periodicals; Biological systems -- Periodicals; 570.5
• DOI: 10.1039/c6ib00105j
• Languages: English
• ISSNs: 1757-9694

Abstract

Abstract : Experimental and computational approaches are used to characterize the macrophage response to opposing activation stimuli. Abstract : Macrophages are versatile cells of the immune system that play an important role in both advancing and resolving inflammation. Macrophage activation has been described as a continuum, and different stimuli lead to M1, M2, or mixed phenotypes. In addition, macrophages expressing markers associated with both M1 and M2 function are observed in vivo . Using flow cytometry, we examine how macrophage populations respond to combined M1 and M2 activation signals, presented either simultaneously or sequentially. We demonstrate that macrophages exposed to a combination of LPS, IFN-γ, IL-4, and IL-13 acquire a mixed activation state, with individual cells expressing both M1 marker CD86 and M2 marker CD206 instead of polarizing to discrete phenotypes. Over time, co-stimulated macrophages lose expression of CD86 and display increased expression of CD206. In addition, we find that exposure to LPS/IFN-γ potentiates the subsequent response to IL-4/IL-13, whereas pre-polarization with IL-4/IL-13 inhibits the response to LPS/IFN-γ. Mathematical modeling of candidate regulatory networks indicates that a complex inter-dependence of M1- and M2-associated pathways underlies macrophage activation. Specifically, a mutual inhibition motif was not by itself sufficient to reproduce the temporal marker expression data; incoherent feed-forward of M1 activation as well as both inhibition and activation of M2 by M1 were required. Together these results corroborate a continuum model of macrophage activation and demonstrate that phenotypic markers evolve with time and with exposure to complex signals.