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      The different faces of the macrophage in asthma

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          Abstract

          Purpose of review

          Asthma is a chronic inflammatory disease in which changes in macrophage polarization have been shown to contribute to the pathogenesis. The present review discusses the contribution of changes in macrophage function to asthma related to polarization changes and elaborates on possible therapeutic strategies targeting macrophage function and polarization.

          Recent findings

          Macrophage function alterations were shown to contribute to asthma pathology in several ways. One is by impaired phagocytosis and efferocytosis. Another is by changing inflammation, by altered (anti)inflammatory cytokine production and induction of the inflammasome. Finally, macrophages can contribute to remodeling in asthma, although little evidence is present in humans yet.

          Novel therapeutic strategies targeting macrophages include dampening inflammation by changing polarization or by inhibiting the NLRP3 inflammasome, and by targeting efferocytosis. However, many of these studies were performed in animal models leaving their translation to the clinic for future research.

          Summary

          The present review emphasizes the contribution of altered macrophage function to asthma, gives insight in possible new therapeutic strategies targeting macrophages, and indicates which knowledge gaps remain open.

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          Most cited references51

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          M-1/M-2 macrophages and the Th1/Th2 paradigm.

          Jesse Alt, C. Mills, K Kincaid … (2000)
          Evidence is provided that macrophages can make M-1 or M-2 responses. The concept of M-1/M-2 fomented from observations that macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more easily activated to produce NO with either IFN-gamma or LPS than macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS stimulates Th2, but not Th1, macrophages to increase arginine metabolism to ornithine. Thus, M-1/M-2 does not simply describe activated or unactivated macrophages, but cells expressing distinct metabolic programs. Because NO inhibits cell division, while ornithine can stimulate cell division (via polyamines), these results also indicate that M-1 and M-2 responses can influence inflammatory reactions in opposite ways. Macrophage TGF-beta1, which inhibits inducible NO synthase and stimulates arginase, appears to play an important role in regulating the balance between M-1 and M-2. M-1/M-2 phenotypes are independent of T or B lymphocytes because C57BL/6 and BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2 proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID macrophages cause CB6F1 lymphocytes to increase IFN-gamma production, while BALB/c SCID macrophages increase TGF-beta production. Together, the results indicate that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur.
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            Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells

            Mirjam Kool, Thomas Soullié, Menno van Nimwegen … (2008)
            Alum (aluminum hydroxide) is the most widely used adjuvant in human vaccines, but the mechanism of its adjuvanticity remains unknown. In vitro studies showed no stimulatory effects on dendritic cells (DCs). In the absence of adjuvant, Ag was taken up by lymph node (LN)–resident DCs that acquired soluble Ag via afferent lymphatics, whereas after injection of alum, Ag was taken up, processed, and presented by inflammatory monocytes that migrated from the peritoneum, thus becoming inflammatory DCs that induced a persistent Th2 response. The enhancing effects of alum on both cellular and humoral immunity were completely abolished when CD11c+ monocytes and DCs were conditionally depleted during immunization. Mechanistically, DC-driven responses were abolished in MyD88-deficient mice and after uricase treatment, implying the induction of uric acid. These findings suggest that alum adjuvant is immunogenic by exploiting “nature's adjuvant,” the inflammatory DC through induction of the endogenous danger signal uric acid.
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              Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction.

              Gaetano Zizzo, Brendan Hilliard, Marc Monestier … (2012)
              Mer tyrosine kinase (MerTK) is a major macrophage apoptotic cell (AC) receptor. Its functional impairment promotes autoimmunity and atherosclerosis, whereas overexpression correlates with poor prognosis in cancer. However, little is known about mechanisms regulating MerTK expression in humans. We found that MerTK expression is heterogenous among macrophage subsets, being mostly restricted to anti-inflammatory M2c (CD14(+)CD16(+)CD163(+)CD204(+)CD206(+)CD209(-)) cells, differentiated by M-CSF or glucocorticoids. Small numbers of MerTK(+) "M2c-like" cells are also detectable among circulating CD14(bright)CD16(+) monocytes. MerTK expression levels adapt to changing immunologic environment, being suppressed in M1 and M2a macrophages and in dendritic cells. Remarkably, although glucocorticoid-induced differentiation is IL-10 independent, M-CSF-driven M2c polarization and related MerTK upregulation require IL-10. However, neither IL-10 alone nor TGF-β are sufficient to fully differentiate M2c (CD16(+)CD163(+)MerTK(+)) macrophages. M-CSF and IL-10, both released by T lymphocytes, may thus be required together to promote regulatory T cell-mediated induction of anti-inflammatory monocytes-macrophages. MerTK enables M2c macrophages to clear early ACs more efficiently than other macrophage subsets, and it mediates AC clearance by CD14(bright)CD16(+) monocytes. Moreover, M2c cells release Gas6, which in turn amplifies IL-10 secretion via MerTK. IL-10-dependent induction of the Gas6/MerTK pathway may, therefore, constitute a positive loop for M2c macrophage homeostasis and a critical checkpoint for maintenance of anti-inflammatory conditions. Our findings give new insight into human macrophage polarization and favor a central role for MerTK in regulation of macrophage functions. Eliciting M2c polarization can have therapeutic utility for diseases such as lupus, in which a defective AC clearance contributes to initiate and perpetuate the pathological process.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Curr Opin Pulm Med
                Journal ID (iso-abbrev): Curr Opin Pulm Med
                Journal ID (publisher-id): COPME
                Title: Current Opinion in Pulmonary Medicine
                Publisher: Lippincott Williams & Wilkins
                ISSN (Print): 1070-5287
                ISSN (Electronic): 1531-6971
                Publication date (Print): January 2020
                Publication date (Electronic): 07 November 2019
                Volume: 26
                Issue: 1
                Pages: 62-68
                Affiliations
                [a ]Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy
                [b ]Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen
                [c ]Department of Respiratory Medicine
                [d ]Department of Experimental Immunology (Amsterdam Infection & Immunity Institute), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
                Author notes
                Correspondence to Barbro N. Melgert, Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Tel: +31 50 3632947; e-mail: b.n.melgert@ 123456rug.nl
                Article
                Publisher ID: MCP260103 Accession ID: 00011
                DOI: 10.1097/MCP.0000000000000647
                PMC ID: 6903353
                PubMed ID: 31703000
                SO-VID: 6dc8f6ad-e4ad-4f73-be7e-1ca51bdae0aa
                Copyright © Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                Categories
                Subject: ASTHMA: Edited by Nicola A. Hanania, Zuzana Diamant, and Maarten van den Berge
                Custom metadata
                OPEN-ACCESS TRUE

                Keywords: efferocytosis,inflammation,innate immunity,phagocytosis
                Data availability:
                Keywords: efferocytosis, inflammation, innate immunity, phagocytosis

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