Macrophages: much more than big eaters!

The Russian bacteriologist Metchnikov described the mac-rophage for the first time in the late 19th century. 1 For his extraordinary contributions to the then burgeoning field of immunology, he was one of the recipients of the 1908 Nobel Prize in Medicine or Physiology. The etymology of the word macrophage, built from the roots makros and phagein, lends insights into the earliest understanding of the function of these captivating cells, that is, the devouring of large structures. We now understand that these big eater macrophages engulf invading pathogens, as well as debris and dead and dying cells. However, beyond roles for these cells in phagocytosis, research has uncovered seminal functions for macrophages in diverse processes, such as development , 2,3 metabolism, 4 and reproduction. 5 Once monocytes are recruited from the circulation into the target tissues, they are transformed into macrophages; these cells are both modulated by and modulate the fundamental phenotypes of the tissues into which they are drawn and then reside. Far from innocent bystanders, macrophages influence major gene programs and functions of the target tissues, for better or for worse. Six contributions have been assembled in this ATVB Miniseries to review how macrophage responses transform the function of diverse tissues in health and disease. Although the traditional term macrophage polarization has been applied to suggest seemingly opposed expression of classical anti-genic markers and functions in these cells, 6 the concept of the extremes of M1 versus M2 polarization, which broadly refers to proinflammatory versus anti/tissue repair functions, respectively, is evolving to a much more comprehensive and dynamic classification in which plasticity and tissue-specific expression and functional patterns are unveiled. In this Miniseries, Leitinger and Schulman 7 explore how macrophage heterogeneity contributes to atherosclerotic lesion development and plaque stability. Bolego et al 8 explore the intriguing connection between the molecular designation of macrophage phenotypes in cardiovascular disease and modulatory roles for estrogen signaling. Might macrophages, in part, explain the protection of premenopausal women to cardiovascular disease? Tugal et al 9 tackle the discussion of the major transcriptional regulatory pathways for macrophage polarization. They review the mechanisms by which complex cross-talk among fundamental biological networks, such as signal transducers and activators of transcription, nuclear factor-κB, interferon regulatory factors, hypoxia-inducible factors, peroxisome proliferator-activated receptors, gluco-corticoid receptors, Krüppel-like factors, microRNAs, and CCAAT/enhancer-binding proteins, orchestrate adaptive and adverse responses to stress. Finally, this Miniseries departs, a bit, from the journal's classical focus on …