White blood cells are cells of the immune system that protect the body from infectious agents.
Macrophages produced upon monocyte differentiation our white blood cells that engulf foreign
materials well known as efficient phagocytes. Macrophages also play a diverse role in various
aspects of the immune response. These macrophages can be found in many tissue types including bone,
brain and even in the peripheral nerves. Upon infection or damage, circulating monocytes
are recruited from the blood, their role is to replenish tissue specific macrophages at sites
of damage and assist in the immune response. Once inside the tissue, local environmental
cues drive these cells to further differentiate into functionally distinct populations. Some will
differentiate into macrophages that secrete pro-inflammatory cytokines for host defense.
Others engage in phagocytosis of cellular debris for tissue repair. Lastly there are
macrophages that produce anti inflammatory cytokines to regulate the immune response.
Our peripheral nerves are fragile and can become damaged as a result of trauma,
disease or surgery. Injury to our peripheral nerves, for instance the intercostal nerves,
will lead to a complex disease known as neuropathic pain. Patients who suffer from this
chronic disease continue to experience stabbing and burning sensations in the absence of stimuli.
Accumulating evidence suggests the interactions between neurons in the damaged peripheral nerve
and macrophages play an important role in the pathogenesis of neuropathic pain. In particular,
two subtypes of macrophages have been discovered within the nerve
at the site of injury. Cytokine secreting macrophages and phagocytic macrophages.
When the peripheral nerve becomes injured or compressed, neurons are damaged both directly
and indirectly. Neuronal function is impaired upon direct damage to axons. Injury to the
Schwann cells that generate the myelin sheaths surrounding the axons, leads to demyelination,
which indirectly hampers neuronal function. It is at this time that nerve resident macrophages
become activated and proliferate. Together with impaired Schwann cells, they secrete mediators
that increase the permeability of the blood nerve barrier, thus promoting the infiltration of
additional circulating monocytes. These ultimately become two subtypes of macrophages : cytokine
secreting and phagocytic. The cytokine expressing macrophages to create proinflammatory mediators to
exaggerate pain signal transmissions to the brain. These mediators can initiate spontaneous firing of
neurons from their sensory nerve endings in the absence of stimuli. The phagocytic macrophages
are responsible for clearing myelin debris. This is absolutely necessary for subsequent regrowth
of axons and remyelination by Schwann cell. Since recovery of damaged nerves may be accelerated by
certain macrophages yet hampered by others, global manipulation of these cells is not a reasonable
treatment for neuropathic pain. Instead, therapeutic treatments that can target and inhibit
the action of the cytokine secreting subtype while preserving the phagocytic macrophages could result
in relief of neuropathic pain and recovery from the disease due to accelerated nerve regeneration.