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action against helminth infection is the “walling off” of Also, the recruitment and/or activation of T regulatory
large bodies through granuloma formation which bears lymphocytes are thought to play a key mediating role
resemblance to the glial scar encountered in central in the “type 2” inflammatory process. [36-38] Indeed,
nervous system (CNS) repair. [27] regulatory T cells have been found not only to be
present in the peripheral circulation of glioma patients
The initiation of the classical inflammatory response is in increased percentages compared to controls, but also
marked by the localization and subsequent activation of to infiltrate glioma tissue in a tumor grade-dependent
blood circulating monocytes into M1 macrophage. The manner. [39,40] Interestingly, some encouraging
M1 macrophage are activated by cytokines produced anti-tumor responses have been obtained in attempts
by Th1 cells, like interferon-γ (IFN-γ), TNF-α, or to neutralize the substantial peripheral regulatory
after recognition of pathogen-associated molecular T cell populations encountered in glioma patients
pattern molecules, through toll-like receptors (TLRs) with systemic administration of TLR ligands. [41,42] For
or C-type lectin receptors. Upon activation, the M1 example, systemic administration of a TLR9 ligand
macrophage promote a proinflammatory environment enhanced survival, decreased the number of peripheral
by releasing cytokines such as TNF-α, IL-1, IL-6, regulatory T cells and enhanced the antigen-presenting
IL-12, IFN-γ, and IL-23. IL-12 stimulates IFN-γ capacity of infiltrating microglia.
production in T lymphocytes and natural killer (NK)
cells. Phenotypically, the M1 phenotype is associated Recently, there have been many studies documenting
[28]
with cell mediated cytotoxicity, tissue injury and a decreased risk of glioma development in individuals
destruction. Thus, the presence of the M1 macrophage with asthma, which is also thought to be driven by
is counter-productive once the invading threat is “type 2” inflammation. [43,44] Reduced immunoglobulin E
neutralized and tissue repair is in order. The resolution levels have been found in patients who developed
of the inflammatory response and transition into glioma. Further, additional studies have found that
wound repair is facilitated by the M2 macrophage. specific polymorphisms in genes encoding IL-4RA
One of the key events leading to immunosuppression and IL-13, both factors that induce IgE production
and activation of “type 2” inflammation is apoptotic in immune cells, are found to be inversely correlated
cell death of recruited neutrophils. [26] The apoptotic with glioma development. This apparent contradiction
neutrophils signal to close classical inflammation can be reconciled by considering the macrophage
and thus modulate immunosuppression after subtype that predominates in each pathology. The M2a
their engulfment by macrophages. In response, macrophage are induced by IL-4 and IL-13, express
the macrophage upregulate expression of the Th2 Fc-epsilon receptors, and are involved in the allergic
anti-inflammatory cytokine IL-10, while significantly response. On the other hand, the M2b macrophage
downregulating the pro-inflammatory cytokines TNF-α, are induced by engagement of the IL-1 receptor and/or
IL-1β, and IL-12. [29] ligation of TLR +/- immune complexes, they express
Fc-gamma receptors and are involved in immune
Several subtypes of the M2 macrophage exist regulation. [45,46] It appears that patients developing
depending on the inflammatory program that is asthma, as a result of hyperactive IL-13 or IL-4 receptor
activated and required. [30] The M2a or alternative signaling, are at lower risk of developing gliomas;
macrophage is activated by the cytokines IL-4 and this may be due to the preferential activation of the
IL-13, and these macrophages are specialized to M2a subset, which may not be as advantageous to the
carry out the allergic response and the killing and developing glioma mass that is dominantly populated
encapsulation of parasites. The M2b macrophage is by the M2b-d macrophage subtypes. IL-10, damage
activated by ligation of TLRs + immune complexes and associated molecular pattern molecules, and IL-6 are
the IL-1 receptor. This macrophage subset is primarily highly expressed in GBM tissue, where they localize
responsible for immune regulation and activation of to the macrophage/microglia population. [31,47-51] Further,
the Th2 program. The M2c macrophage, activated it has been shown that the presence of IL-4 or IL-13
by the cytokine IL-10, is primarily responsible for inhibit the proliferation of astrocytes and low-grade
matrix deposition and tissue remodeling. Recently, a astrocytomas, but not GBM. [52]
fourth and distinct subtype, termed the M2d subset,
has been identified. This subset is activated by In glioma tissue, macrophages/microglia can account
IL-6 and is thought to aid in tumor metastasis and for up to 30% of the total lymphocytic infiltrate
progression. [31] The primary cells responsible for present in the tumor mass. [53,54] It is now accepted
the synthesis of those cytokines are eosinophils, that the macrophage and microglia populations found
basophils, and CD4 Th2 cells, and tumor cells. [32,33] within glioma originate from distinct progenitor cell
+
M2 macrophage down-modulate the release of IL-1, populations. Infiltrating macrophages are derived from
IFN-γ, IL-12, and TNF-α. [34,35] the bone marrow, whereas microglia are brain-resident;

68 Neuroimmunol Neuroinflammation | Volume 1 | Issue 2 | September 2014