Macrophages at the Fork in the Road to Health or Disease

摘要

Macrophages are the epicenter of all immune systems ( 1 ). The first and the most abundant leukocyte observed ( 2 ), macrophage have long been relegated to the role of “servants” of T or B cells/adaptive immunity. This view is now known to be backward. Macrophages necessarily initiate and direct virtually all immune responses from simple multicellular animals to humans.There is good news and bad news in the newly recognized importance of macrophages/innate immunity. The well-known “double-edged sword” nature of the immune system can largely be attributed to macrophages’ unique ability to make polar-opposite repair/heal (M2) or kill/inhibit (M1) type responses ( 3 ).In health, M2-type macrophages maintain homeostasis by helping repair and replace lost or effete cells. Ever-present in tissues, macrophages are also the primary host defense against pathogens (or altered self cells) because their unique physiology allows them to rapidly switch from their M2/heal mode to an M1/inhibit mode: both powerful responses; both potentially dangerous.In disease, over expression of M2/heal macrophages contributes to chronic infections, fibrosis, allergy, and cancer ( 3 ). Conversely, M1/inhibit-dominant activity plays a major role in atherosclerosis, autoimmunity, and other chronic inflammatory conditions.Of fundamental importance is that both the routine M2/heal and the induced M1/inhibit macrophage functions occur in all animals whether they have T cells or not. Furthermore, M1 and M2 macrophage responses play necessary roles in causing T cells to make Th1 or Th2-type responses if pathogens or altered self are present ( 4 ). Hence, the renaming of macrophage responses M1 and M2.This new knowledge about the central role of macrophages in immune systems brings great promise for increasing health/decreasing disease. In this regard, the ability of macrophages to exhibit the polar-opposite M2/heal and M1/kill functions result, in part, from their unique ability to metabolize one amino acid – arginine – to either growth-promoting ornithine or growth-inhibiting nitric oxide (NO) ( 5 ). Hence, the title of this Topic, “M1 and M2 Macrophages: The Arginine Fork in the Road to Health and Disease.” We hope that the articles assembled here help illuminate the basic functions of macrophages referred to as SHIP [sample, heal, inhibit, and present (antigen)]. Such knowledge is critical for developing the means to modulate the direct M2/heal or M1/inhibit responses of macrophages, or their indirect abilities to initiate and direct T and B cell responses. One can properly say macrophages are the “chicken and the egg” of immunity ( 1 ). Origin of M1/Inhibit and M2/Heal Macrophages and the Scope of the Topic As an introduction to M1 and M2 macrophages, a chronology of results (and publications) that led to their discovery is summarized below: Macrophages have the unique ability to produce a growth-inhibiting molecule (NO) or a growth-promoting molecule (ornithine), through the enzymatic conversion of l -arginine in different ways ( 6 – 8 ). Macrophages in normal tissues, healing wounds, or in growing tumors metabolize arginine primarily to ornithine via arginase (later to be named M2-type). Macrophages can switch to producing NO via iNOS (to be named M1-type) that is necessary to kill cancer or many pathogens. Arginine is the source of both ornithine and NO ( 9 – 12 ). Macrophages were specifically renamed M1 and M2 to highlight that innate immunity controls adaptive immunity. M1 (NO) or M2 (ornithine)-type macrophage responses are T cell independent and they stimulate Th1-type and CTL responses, or Th2-type responses, respectively ( 1 , 3 – 5 ). Thus, M1/M2 represents a sea change in our understanding of how immune responses occur. These studies have stimulated thousands of publications that have enhanced our knowledge of the importance of M1/inhibit and M2/heal functions, and other cytokines and factors that accompany these responses ( 1 ). Here, we have assembled papers by contributors that focus on basic aspects of macrophage biology, their roles in various diseases, and how they are regulated. Macrophages evolved long before other immune cell types and are the foundation of all animal immunity ( 13 ). Therefore, we begin with a series of “introductory” articles where readers can find basic information about macrophage biology and functions. These articles also trace the evolutionary origins of macrophages to aid in understanding their central role in immune systems. Next, articles detail the roles of macrophages in protection against (or causation of) various diseases including wounds, cancer, infections, atherosclerosis, obesity, hypertension, and other conditions. Finally, we look to the future with several articles detailing how macrophage M1/inhibit and M2/heal functions might be modulated for therapeutic benefits. We hope that the articles enhance your knowledge of this singularly multitalented and remarkable leukocyte. Introduct