The M1 and M2 paradigm of macrophage activation: time for reassessment

Summary: During development and throughout adult life, macrophages derived from hematopoietic progenitors are seeded throughout the body, initially in the absence of inflammatory and infectious stimuli as tissue‐resident cells, with enhanced recruitment, activation, and local proliferation following injury and pathologic insults. We have learned a great deal about macrophage properties ex vivo and in cell culture, but their phenotypic heterogeneity within different tissue microenvironments remains poorly characterized, although it contributes significantly to maintaining local and systemic homeostasis, pathogenesis, and possible treatment. In this review, we summarize the nature, functions, and interactions of tissue macrophage populations within their microenvironment and suggest questions for further investigation.

Macrophages are present in all vertebrate tissues, from mid-gestation throughout life, constituting a widely dispersed organ system. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes in defence against microbes and in clearance of dead and senescent cells, but also through trophic, regulatory and repair functions. In this review, we describe macrophage phenotypic heterogeneity in different tissue environments, drawing particular attention to organ-specific functions.

As we approach the centenary of Elie Metchnikoff's Nobel Prize (1908), it is opportune to reflect upon the history of macrophage immunobiology, take stock of current knowledge and anticipate questions for the future. Starting from his appreciation of phagocytosis as an important determinant of host defence against infection and injury, we have learned a great deal about the distribution of macrophages throughout the body, their heterogeneous phenotype and complex functions in tissue homeostasis as well as in innate and acquired immunity. Recent discoveries of Toll‐like and other plasma membrane, vacuolar and cytosolic recognition molecules have brought the macrophage and closely related dendritic cells to the centre of immunologic attention, but many earlier discoveries of their cellular and molecular properties have laid a broader foundation to the appreciation of their remarkable plasticity and adaptability to local and systemic cues. Discoveries of pro‐inflammatory mediators such as TNF and other secretory products have provided valuable insights into the role of macrophages in many acute and chronic disease processes, and led to the development of effective therapeutics. Much remains to be discovered regarding both their specific functions and by study of their general cellular properties, in vitro and in vivo.