In moving through the components of the innate immune system, some aspects will seem quite
abstract and foreign, like the complement system we just learned about. But the next phenomenon
we will investigate is something that everyone is familiar with, and that is inflammation, which is
a complex immune response to harmful stimuli. Imagine that you visit the doctor with a sore
throat. When the doctor examines your throat, they declare, “Yep, that definitely looks inflamed.”
But how can they tell that there’s inflammation going on inside some tissue just by looking?
There are five classical signs of inflammation. The first four were described by the Roman
encyclopedist Celsus in the first century CE as: pain, or in Latin, dolor, redness or rubor,
swelling or tumor, and heat or calor. A fifth sign, loss of function, was added later.
“Inflammation” is sometimes used as a dirty word within the medical and pop science realms, whereby
health coaches and social media influencers are full of suggestions for what you should
eat or how you should exercise in order to “reduce inflammation.” While chronic inflammation can have
devastating side effects, acute inflammation is an important evolutionary adaptation
that is extremely effective at containing the early spread of infectious microbes.
Acute inflammation plays three main roles during an infection. One: to destroy invading microbes.
Two: to induce local blood clotting to reduce the spread of infection through the bloodstream.
And three: to repair injured tissue. Let’s focus on describing the process of
acute inflammation. Acute inflammation is made up of two major components: the vascular component,
and the cellular component. The term “vascular” refers to the blood vessels,
which are made up of endothelial cells surrounded by smooth muscle. Since blood vessels permeate
every tissue, carrying circulating immune cells and important plasma mediators, like complement
which we just learned about, the vasculature is a critical player in controlling an infection.
The very first step in an inflammatory response is the sensing of tissue damage or
microbial infection by tissue-resident immune cells, or by the cells that make up a tissue.
Remember that pattern recognition receptors can recognize microbial patterns found on infectious
microbes called PAMPs, as well as signs of tissue damage that might result from a burn
or blunt force trauma, called DAMPs. Activated macrophages release inflammatory lipid mediators
like leukotrienes, prostaglandins, and platelet-activating factor,
as well as other chemicals like nitric oxide. These inflammatory mediators
act on the smooth muscle cells surrounding the vasculature to induce vasodilation,
which is a widening of the blood vessels. Vasodilation increases the volume of blood
while slowing down blood flow, and is responsible for the redness and heat that often accompanies
inflammation. The slowed blood flow helps slow the spread of the pathogen through the bloodstream,
and enables immune cells in the blood to leave the circulation and enter the affected tissue.
Nitric oxide and other mediators also increase vascular permeability, which we can think of
as leakiness, that occurs when the normally tightly-joined endothelial cells separate from
each other to produce gaps. Increased vascular permeability means that fluid from the blood
leaks into the tissues, and this is the cause of swelling that is often seen during inflammation.
The local influx of fluid and plasma proteins like complement and antibodies helps concentrate
these proteins in infected tissue. We have already discussed the complement system, which helps clear
infectious microbes. However, there are other important protein cascades that are mediated by
plasma proteins. One of these is called the kinin system. The kinin system is similar
to complement in that it is a protease cascade which involves a sequence of proteins cleaving
and activating other proteins. Bradykinin is one of the terminal products of the kinin system.
It is a 9-amino acid peptide that increases vascular permeability and promotes pain sensing.
Another important plasma protein cascade is the coagulation system, that results in a fibrin clot.
Of course, blood clotting is important when there is an actual wound and someone
needs to stop bleeding. However, local blood clotting in the microvessels of inflamed tissue
also helps prevent the spread of pathogens through the bloodstream,
and some pathogens can even be trapped inside fibrin clots.
The changes that occur to endothelial cells during inflammation result in endothelial activation.
In addition to the pathways we’ve already discussed, activated endothelial cells
also increase expression of cell adhesion molecules on their luminal side,
which is the side facing the inside of the blood vessels. Expressing cellular adhesion molecules
allows the vascular component to interact with the cellular component of inflammation,
since circulating immune cells have to interact with the endothelium to move into tissues.
Here’s how this process works. Endothelial cells express a protein on their surface called
P-selectin in response to the cytokine TNF-alpha, bacterial endotoxin, leukotriene B4, histamine,
or complement protein C5a. They also express a protein called E-selectin.
These selectins recognize and bind to glycoproteins on the surface of immune cells.
As blood flow through a vessel slows due to vasodilation, immune cells,
especially neutrophils and monocytes, are able to move to the walls of the blood vessels,
where they can begin to interact with the selectins. Instead of flowing through the
blood vessels, these immune cells begin to roll along the edge of the blood vessel,
kind of like a nervous ice skater clinging to the edge as they move around the rink.
Eventually, the immune cell will express adhesion molecules like LFA-1 and CR3, which interact with
ICAM-1 and ICAM-2 on endothelial cells. Chemokines like CXCL8, which are increased
during inflammation, strengthen these interactions between immune cells and endothelial cells until
the immune cell completely stops rolling and is stuck to the outside of the endothelium.
Here, the immune cell extravasates, or moves between endothelial cells to get into the tissue.
To do this, PECAM-1 or CD31 on immune cells binds to PECAM-1 on endothelial cells,
and the immune cells squeeze between the endothelial barrier into the tissue.
From here, the immune cell can rely on chemotaxis in response to local molecular signals like
chemokines to find the affected tissue site. Within the tissue, cells can engage
in the cellular component of inflammation. This component includes actions like phagocytosis,
which is enhanced by opsonization of the target with complement and antibodies. It also includes
release of pro-killing effectors such as lysozyme, granzyme B, nitric oxide, interferon-gamma,
as well as propagation of the immune response through release of other cytokines and chemokines.
Many cells involved in the cellular component are also critical for repairing tissue damage.
The acute inflammatory response is an effective way to limit microbial spread
and promote wound healing. But it’s extremely powerful, and isn’t meant to be switched on for
too long. Although many antimicrobial mechanisms are specially designed to only target pathogens,
several can cause collateral damage to host tissue. Typically, following an acute inflammatory
response, there should be a resolution stage, where a new suite of regulatory molecules sweeps
in to control the immune response. Previously, it was believed that an inflammatory response
was self-limiting and just died off when it was no longer receiving appropriate stimulation. However,
more recent research has shown that resolution is an active process that uses several distinct
mechanisms and mediators to decrease inflammation and promote wound healing.
One feature that helps promote resolution of inflammation is the short half-life of
neutrophils, which are one of the first and most abundant cell types to appear on the scene
during an infection. Neutrophils begin to undergo apoptosis after just a few days of being in the
tissue, and they are phagocytosed by infiltrating macrophages in a process called “efferocytosis.”
The process of efferocytosis can help reprogram macrophages to be less pro-inflammatory
and to be more pro-resolving, meaning that they’ll make fewer inflammatory cytokines,
becoming more involved in clearing out dead cells and producing the kind of cytokines that promote
wound healing. Just as the prostaglandins and leukotrienes are lipid mediators of inflammation,
there are several classes of lipids involved in resolution.
These mediators are derived from polyunsaturated fatty acids, and include resolvins, protectins,
lipoxins, and maresins. These lipids have a huge range of pro-resolving effects,
which include production of anti-inflammatory cytokines like IL-10, stimulating efferocytosis,
decreasing neutrophil chemotaxis towards a chemical gradient, decreasing expression of
adhesion molecules on endothelial cells, and decreasing vascular permeability.
The resolution phase also involves repair of damaged tissue, which includes angiogenesis,
meaning the growth of new blood vessels, proliferation of epithelial cells, and deposition
of extracellular matrix proteins like collagen to restore the tissue to its proper function.
When a tissue doesn’t go through this resolution phase, however, either because
of an inability to clear the pathogen, tissue damage that perpetuates the immune response,
or something else, the result is chronic inflammation. Chronic inflammation can
lead to extremely negative consequences like scarring or non-healing wounds and ulcers.
A chronic inflammatory environment can also help promote cancer.
Like everything else in immunology, or perhaps biology in general, the key is always balance.
A balanced inflammatory response will be strong enough to contain and eliminate pathogens,
while resolving properly so that the tissue can heal and return to homeostasis.
And that concludes an introduction to the inflammatory response.