Macrophages
are cells of the immune system that, in addition to playing an
essential role in the early response to microbial infection, also
regulate tissue function and inflammation. Inflammation is a
physiological response that helps to repair damaged tissue, but if not
correctly resolved it can become chronic inflammation, which lies at the
origin of many conditions, including the metabolic syndrome associated
with obesity, type 2 diabetes, and cardiovascular disease.
Now,
a research team has discovered that the metabolic requirements of
macrophages differ depending on the organ in which they reside. In other
words, these cells adapt to the needs of the organ in which they are
located. The discovery “gives us a better understanding of how
macrophages regulate their metabolism according to the organ in which
they reside. In addition, our results reveal a vulnerability of
macrophages that contributes to chronic inflammatory diseases and that
could be exploited therapeutically for the treatment of conditions
associated with obesity and metabolic syndrome, such as cardiovascular
disease,” said the study leader. The study is published in an article in
the journal Immunity.
Macrophages
are immune cells that are normally distributed throughout the body and
help to cleanse organs of all types of biological material that needs to
be removed, from harmful particles such as mineral crystals or viruses
to proteins or larger complexes that arise during development.
Macrophages are also important for removing dead cells, thus
contributing to tissue renewal. The new study reveals that macrophages
adapt their metabolism and function to the organ in which they reside.
“In
tissues with abundant extracellular fat and cholesterol, such as the
lungs and spleen, macrophages adapt their metabolism to degrade these
fats through mitochondrial respiration,” explained the first author.
“Using genetic or pharmacological methods to disrupt mitochondrial
respiration, mitochondria can be eliminated from lung and spleen,
whereas the macrophages in other organs, which don’t depend on
mitochondrial respiration, survive.”
Another
example is provided by the macrophages located in body fat, or adipose
tissue. “Macrophages residing in the body fat of a person of normal
weight are unaffected by mitochondria-disrupting treatments because
their metabolism is less dependent on mitochondrial respiration. This is
because the fat cells, called adipocytes, are fully functional, leaving
the macrophages in a resting state,” said the first author. “However,
in obese individuals, the excess fat surpasses the capacity of the
adipocytes, and the resident macrophages become activated, converting
into inflammatory cells that promote the development of insulin
resistance, type 2 diabetes, and fatty liver.”
But
this change in adipose tissue macrophages also makes them vulnerable.
“The activated macrophages depend on mitochondrial respiration to
process the excess fat, and this makes them vulnerable to therapeutic
interventions, including pharmacoligical inhibitors of mitochondrial
respiration,” explained the author.
The
Immunity study shows that inhibition of mitochondrial respiration
killed these proinflammatory macrophages, preventing the progression of
obesity, type 2 diabetes, and fatty liver (the key components of
metabolic syndrome) in an experimental mouse model. The investigators
conclude that this finding opens the way to new treatments for
conditions linked to obesity and metabolic syndrome, like cardiovascular
disease.
https://www.cell.com/immunity/fulltext/S1074-7613(23)00021-3