Investigators at the University of California, San Diego (UCSD) School of Medicine have described the first organ-specific intrinsic immune system:
Macrophages are white blood cells involved in the inflammatory response throughout the body, cells normally on the alert for invaders to kill. Alveolar macrophages are unique among macrophages in the body, because their activation is inhibited by TGFb, a compound expressed in the lung by epithelial cells.
“Because the microenvironment of the alveola is a delicate one, it would be damaged if the macrophage immune system was in a constant battle-ready status,” said Raz. “This could readily lead to the type of inflammation we see in autoimmune diseases of the lung such as asthma.”
Therefore, the alveola possess a complex immune system in which the macrophage is repressed in its steady state, activated when called upon to fight invading microorganisms, and then re-repressed, in a circuit that is unique to this microenvironment.
“Dissecting this immune mechanism provides us with the knowledge of how we might prolong the activation status of alveolar macrophages. This knowledge could prove to be essential in combating any novel microbial agents that could infect the lower airways, such as a new flu strain or bioterrorist agents,” said Raz.
The researchers’ data outlines a complex circuit in which the alveolar macrophages circumvent the inhibition by TGFb for brief period of time, in order perform their immune task. This is accomplished through regulation of TGFb activity by a set of cell surface receptors, proteins called integrins.
This regulation allows the alveolar macrophages to take on their “killer” function – the ability of macrophages to engulf invading microorganisms – but only for a very limited period of time. The mediating role of TGFb, briefly inactivated by the integrin, is then restored by one of the lung’s own enzymes, the MMP9.
“Basically, the macrophages wake up for a while, but the system’s own enzymes activate the inhibitor that puts them back to sleep,” said Kenji Takabayshi, Ph.D., first author of the study.