About Immunity

(6) Stages of macrophage activation

LPS activates macrophages. Many people question whether inflammation is caused by activating macrophages. Here, we will explain the activation of macrophages.

Macrophage activation has stages and directions as shown in the figure below.

Ingested LPS activates macrophages in the mucous membrane of the digestive tract from the oral cavity. Strictly speaking, it activates the priming state, which is a standby state that can quickly switch to a “fighting macrophage” stage when a fighting opponent is introduced and to a “calming macrophage” stage when there is a healing site (*1). Whether the macrophage switches to a “fighting macrophage,” a “calming macrophage,” or “remains in the priming state” depends on the signal transmitters of the contact target and fellow immune cells.

On the other hand, when LPS is injected into the blood, macrophages in the blood are simultaneously activated by “fighting macrophages.”

Why are the reactions different? Mucosal and blood macrophages have different responsiveness to LPS. The area between the oral cavity and the digestive tract is where bacterial components are consumed with food. In addition, several intestinal bacteria live in the large intestine. Therefore, mucosal macrophages do not immediately become “fighting macrophages” even when they encounter LPS, which is a bacterial component, and are designed to remain in a priming state (*2).

The inside of the blood vessel is a sanctuary. Blood macrophages are designed to immediately become “fighting macrophages” against bacteria and bacterial components and produce an elimination reaction (however, if the amount of LPS is very small, it acts as a primer).

Of note, activation is a term that includes the priming state as described above. LPS that enters via the mouth activates mucosal macrophages to the priming state, so it does not induce inflammation.

So what is the significance of priming macrophages?

The situations where macrophages have a function are: 1) When they find a bacterium or virus in an area in the body where they should not exist (for example, in the blood or an organ, such as the liver or lungs) 2) When they find that your cells have become abnormal due to infection with bacteria or viruses 3) When your cells show a mark of cancer on the cell membrane 4) When your cells have a dead mark on the cell membrane 5) When they discover a protein that has become vulnerable to oxidation, glycation, or cleavage 6) When they receive a signal from another immune cell that there is a foreign body In such situations, macrophages first respond via an eating process (called phagocytosis), and when necessary, secrete cytokines, which are information mediators, and inform the immune cells about their friends.

When they encounter the above situation, it is important that macrophages respond quickly. Whether fighting or calming down, the response should not be delayed. For this, it is ideal that macrophages are always in a primed state. However, the condition of these macrophages often decreases to low levels due to aging and stress.

If you often have a cold, wounds do not easily heal when you get hurt or you may have an illness that will not allow you to become better. In such cases, it is possible that the innate immunity led by macrophages is weakened. Thus, orally consuming LPS is a safe and effective method for activating (priming) macrophages (*3).

（*1）Alveolar macrophage phagocytic activity is enhanced with LPS priming, and combined stimulation of LPS and lipoteichoic acid synergistically induce pro-inflammatory cytokines in pigs. Innate Immun 19: 631-643 (2013)
（*2）Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bactericidal activity. J Clin Invest115: 66-75 (2005)
（*3）Oral administration of lipopolysaccharides for the prevention of various diseases: benefit and usefulness. Anticancer Res 31: 2431-2436 (2011)