Page 6 - Read Online

Page 74 Tanaka. Neuroimmunol Neuroinflammation 2020;7:73-91 I http://dx.doi.org/10.20517/2347-8659.2020.04

including cytokines, growth factors, and reactive oxygen/nitrogen species, and phagocytosing degenerating
[1-4]
cells and materials . In this article, we use “microglia” to denote resident microglia in the CNS, and
“macrophages” to denote cells derived from circulating monocytes that have invaded (typically inflamed)
CNS lesions with a disrupted blood-brain barrier (BBB). The two types of mesoderm-derived cells share
[5,6]
many kinds of characteristics and surface antigens . In particular, when microglia become activated in
response to severe pathologic events, such as stroke or traumatic brain injury (TBI), which accompany
BBB breakdown, both cell types resemble each other in terms of morphology, functions, and cell marker
[7]
expression. The term “amoeboid microglia” has long been used to denote extremely activated microglia
displaying almost the same morphology as brain macrophages in severe lesions. Therefore, it is generally
difficult to distinguish one from the other. This assumption originated from the historical observation by
[8]
Rio-Hortega , who reported that ramified microglia in the normal mature brain can, in severely damaged
brains, turn into phagocytes exhibiting spherical shapes of the same morphology as that of blood-borne
[5]
macrophages . Therefore, numerous studies have described CD11b-expresssing (in the case of the rat brain,
a monoclonal antibody OX-42-immunoreactive) spherical cells in severely injured brains in the acute phase
as activated microglia, although most of them should be recognized as invading neutrophils [9,10] .

More recently, it is well-known that both cell types play major roles in pathophysiological processes [2,11,12] .
The neuroinflammatory processes influence outcomes of CNS diseases or injuries in both favorable and
unfavorable ways. In this review, “favorable” is used to describe microglia and macrophages that are
neuroprotective cells bringing about the better outcome in the pathologic CNS than “unfavorable” ones
that exert deleterious effects on the survival of neurons and other parenchymal cells. Therefore, various
kinds of interventions, including pharmacological treatment and rehabilitation, have been studied in
laboratory and clinical settings to determine if they enhance favorable responses while also suppressing
the deleterious effects of microglia and macrophages [1,4,13,14] . This aim may be interpreted as attempting
to induce M2-polarized or alternatively activated phenotypes of these cells [15-17] . However, phenotypes
of activated microglia and macrophages cannot be classified clearly into M1-polarized or M2-polarized
cells [18,19] .

Diseases and injuries of the CNS can be categorized by the absence of BBB disruption [20,21] . In the absence
of BBB disruption, the infiltration of circulating leukocytes is limited, and microglia play a central role
as immune cells. When the BBB is disrupted, infiltrating leukocytes play much more significant roles [9,22] .
In particular, invading monocytes increase hugely in number because of their strong proliferative nature
and end up occupying almost the entire area of the lesion in either stroke or traumatic injury [11,12] . Marked
accumulation of blood-borne macrophages is seen in malignant brain tumor masses, which are termed
tumor-associated macrophages [23,24] . Tumor-associated macrophages contribute to tumor growth and
angiogenesis by secreting many kinds of growth factors, including vascular endothelial growth factor.
Tumor-associated macrophages are not discussed in this article.

Thus, microglia and macrophages are the critical cells in CNS diseases and injuries and have a profound
impact on patient outcomes. Therefore, many studies have investigated interventions to both suppress the
unfavorable effects of microglia and macrophages and induce their favorable functions. This article also
deals with several interventions targeting microglia and macrophages. There are three types of resident
macrophages that are distinct from microglia and the invaded blood-borne macrophages. Those are the
meningeal, perivascular and choroid plexus macrophages. Although they play significant roles in health
and pathology, they are not discussed in this review.

DISTINGUISHING BETWEEN MICROGLIA AND MACROPHAGES
Discriminating microglia from macrophages has been considered to be very difficult. This is partly due to
the old notion that microglia in the brain are derived from circulating monocytes [7,25] . Moreover, microglia