M1 and M2 macrophages: the chicken and the egg of immunity

Abstract

The purpose of this perspective is to describe a critical advance in understanding how immune responses work. Macrophages are required for all animal life: 'Inhibit' type macrophages in all animals (called M1) can rapidly kill pathogens, and are thus the primary host defense, and 'Heal' type macrophages (M2) routinely repair and maintain tissue integrity. Macrophages perform these activities in all animals without T cells, and also in T cell-deficient vertebrates. Although adaptive immunity can amplify macrophage polarization, the long-held notion that macrophages need to be 'activated' or 'alternatively activated' by T cells is incorrect; indeed, immunology has had it backward. M1/M2-type macrophages necessarily direct T cells toward Th1- or Th2-like activities, respectively. That such macrophage-innate activities are the central directing element in immune responses is a dramatic change in understanding how immune systems operate. Most important, this revelation is opening up whole new approaches to immunotherapy. For example, many modern diseases, such as cancer and atherosclerosis, may not display 'foreign' antigens. However, there are clear imbalances in M1/M2-type responses. Correcting such innate imbalances can result in better health. Macrophages are the chicken and the egg of immunity.

Fig. 1

a M1- or M2-dominant macrophages stimulate Th1- or Th2-like T cell responses that further amplify M1/M2-type responses. b The characteristic products and functions of M1/inhibit and M2/heal macrophage responses. Other products have been variously observed during both M1 and M2 responses. Mice do not have IL-8; their M1 macrophages express CXCL1 and CXCL2 instead. orn = Ornithine.

Fig. 2

Macrophages initiate and direct virtually all immune responses. They are the center of the immune ‘Solar System’. CTL = Cytotoxic T lymphocyte.

Fig. 3

Macrophages in vertebrates possess four basic functions that allow them to maintain host tissue homeostasis and respond to infectious or noninfectious threats in a variety of ways to optimize host protection. These functions are sample, heal, inhibit and present (antigen). CTL = Cytotoxic T lymphocyte.