The evolution of our understanding of macrophages and translation of findings toward the clinic

Abstract

‘There is at bottom only one genuinely scientific treatment for all diseases, and that is to stimulate the phagocytes,’ so declaimed Sir Ralph Bloomfield Bonington in The Doctor’s Dilemma, Act 1, by George Bernard Shaw (1906). More often nowadays, the need is to calm the phagocytes, given their role in inflammation and tissue damage. In spite of the growth of cellular and molecular information gained from studies in macrophage cell culture, mouse models and, to a lesser extent, human investigations, and the importance of macrophages in pathogenesis in a wide range of chronic disease processes, there is still a substantial shortfall in terms of clinical applications. In this review, we summarize concepts derived from macrophage studies and suggest possible properties suitable for diagnosis, prognosis and selective targeting of macrophage pathogenic functions.

Keywords:

• activation
• biomarker
• cytokines
• immunity
• inflammation
• macrophage
• monoclonal antibody
• monocyte
• phagocytosis
• targeting

Acknowledgements

We thank the following colleagues for advice: F Cannone-Hergaux, A Cerami, R Choudhury, M Collin, A Doyle, D Greaves, D Hume, D Hughes, M Khati, G Kaplan, C Nathan, M Netea, T Lawrence, L Peiser, H Rosen, K Shokat and S Wright.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Most of our knowledge is derived from studies in the mouse system: human and other relevant animal models are needed to close the gap between the bench and the clinic.

• Until now, efforts to understand macrophage heterogeneity and activation in human tissue are scarce: there is a need for integration of molecular, cellular and systemic efforts and relevant research disciplines.

• Access to human tissue samples for research is limited, lengthy and bureaucratic and should become a priority.

• Macrophage heterogeneity varies with origin, activation and tissue localization/microenvironment and needs to be teased out to achieve selective targeting. Unlike T and B cells, macrophages do not form categoric subsets after activation and single genetic and phenotypic markers are rarely informative: methods to measure multiple genes, proteins and metabolites in situ need to be integrated.

• Diagnostic and prognostic value of macrophage-specific biomarkers requires validation from early pathogenesis to late stages of disease.

• Our knowledge of macrophage functions within the body is incomplete: novel ex vivo assays will inform drug development and clinical pathology.