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First, human Macrophage can’t randomly engulf cells/bacteria/debris. Macrophages engulf entities coated with eat-me signals. These include specific cell-surface molecules, complement proteins (Complement system) and antibodies, the latter two part of the opsonization process (Opsonin). Meaning other systems need to engage before a pathogen can be engulfed by macrophages. In some cases, complement needs to be activated and its proteins need to coat it. In others, B cells specific for antigens expressed by the pathogen need to be activated, helped by T cells, and secrete antibodies that can specifically bind to and coat it. This simplified summary already reveals the limitation of thinking that macrophages, as part of the innate immune system, engage first, and that the adaptive immune system engages later. While some elements of the innate immune system, such as neutrophils and dendritic cells, are indeed among the first to engage, the proper functioning of the immune system doesn’t follow a strictly cartoonish linear sequence of innate first, adaptive second. A much too complex and multi-factorial system such as immunity cannot be so strictly linear.

Second, while it would certainly be simpler if macrophages could simply engulf and neutralize every pathogen our body encountered, the problem is how to distinguish pathogen from benign/commensal/mutualist microbes. Post-birth, our body is host to trillions of microbes, majority of whom are benign, even important for our normal physiology. Many of their cellular components overlap with those of pathogens so a macrophage can’t distinguish between the two without contextual signals. This brings us back to the first issue, namely that macrophages need help from other components of the immune system to figure out who to eat (engulf).

Third, while macrophages can directly engulf extracellular bacteria, fungi, Protist, the issue’s much more complicated with intracellular bacteria and viruses. In their case, macrophages would need to engulf bacteria/virus-infected cells to get rid of them, i.e., indirect engulfing, again something that requires contextual signals.

Thus far, this is the situation with human macrophages and the immune system they function in. What about invertebrates? They lack an adaptive immune system (AIS). Do their macrophages perform such a function? Answer’s not so linear and straightforward since invertebrates aren’t simply vertebrates minus AIS. Germane to immune function, many invertebrates appear to have evolved physical barriers limiting their contact with the outside world, specifically the intimacy of their association with the microbial world. This difference in kind is the basis for Margaret McFall-Ngai’s theory that vertebrate AIS evolved in response to much more intimate symbiotic relationships with microbiota (1).

Another hypothesis, highlighting the many similarities between digestion and defense, argues these two systems have a common origin (2). Adding to the second idea, a third hypothesis argues that evolution of the energetically highly demanding AIS was made possible by development of adipocytes (fat-storing cells) which expanded the body’s ‘metabolic scope‘ hence creating an energy milieu that could support the evolution of the AIS (3).

While all three are theories, they make interesting arguments for how evolution co-opts ancient cells and proteins for new functions. As Élie Metchnikoff proposed more than a hundred years back, phagocytes such as macrophages evolved for digestion and became co-opted for defense, since evolution of multi-cellularity enabled functional specialization. As such, human macrophages and phagocytic function of single-celled organisms like amoeba are linked through evolution but now perform very different functions in very different bodies.


  1. McFall-Ngai, Margaret. “Adaptive immunity: care for the community.” Nature 445.7124 (2007): 153-153. Page on wisc.edu
  2. Broderick, Nichole A. “A common origin for immunity and digestion.” Frontiers in immunology 6 (2015). Page on nih.gov
  3. Van Niekerk, Gustav, and Anna-Mart Engelbrecht. “A Commentary on “A common origin for immunity and digestion”.” Frontiers in Microbiology 6 (2015): 531. Page on frontiersin.org