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Page 152 Harry et al. Neuroimmunol Neuroinflammation 2020;7:150-65 I http://dx.doi.org/10.20517/2347-8659.2020.07

SENSING AND RESPONDING TO THE ENVIRONMENT
While microglia appear to be tightly adapted to the specific requirements within brain regions, they all
function in a surveillance mode with mobile processes extending into the surrounding microenvironment
to detect tissue changes [31,32] . Upon sensing such changes, microglia respond to their environment via
several “sensome” genes, allowing them to sense and interact with their local environment [8,14,33] . These
sensome genes include those for putative purinergic receptors, P2ry12 and P2ry13, transmembrane protein
119 (Tmem119), G-protein coupled receptor 34 (Gpr34), the C-type lectin receptor, the fractalkine receptor,
Cx3cr1, sialic acid-binding immunoglobulin-type lectin H (Siglec-h), and triggering receptor expressed on
myeloid cells 2 (Trem2). Siglec proteins contribute to immune regulation by binding sialic acid residues
[34]
on neurons and TREM2 contributes via recruitment of the immunoreceptor tyrosine-based activation
[35]
motif-containing adapter protein, DAP-12 . The final response of the cell is dictated by the overall pattern
of sensome gene activation.

The microglia host-response begins with the recognition of pathogen-associated molecular patterns
(PAMPs) such as bacterial, viral, and protozoal products (protein lipid, nucleic acid, and carbohydrate). This
[36]
occurs via pattern recognition receptors on the plasma membrane or in the endosomal compartments , or
[37]
by binding phagocytic scavenger receptors and macrophage antigen complex I (MAC1, CD11b/CD18),
[38]
which is a pattern recognition receptor linked to the superoxide-generating enzyme NADPH oxidase .
In the absence of microorganisms, a similar but sterile inflammatory response occurs often as a result of
trauma, ischemia-reperfusion injury, or chemical exposure [39-41] . Activation in the absence of microbial
[42]
compounds occurs by endogenous molecules called danger-associated molecular patterns (DAMPs) .
Molecules that function as DAMPs include nucleic acids, lipids, and proteins that normally are not present
to immune cells until released or unmasked during cell death due to tissue injury. In the CNS, microglia
responding in various neurodegenerative diseases in the absence of pathogen have been termed disease-
associated microglia (DAM). Intracellular DAMPs include high mobility group box 1 (HMGB1) and
peroxiredoxin family proteins. These damage signals can activate immune cells through three major
families of intracellular recognition receptors: toll-like receptors, nucleotide-binding domain leucine-
rich repeat containing proteins (also known as NOD-like receptors), and Rig1-like receptors. Receptor
activation induces specific pathways and the release of cytokines that contribute to injury mitigation .
[43]
Microglia are influenced by a plethora of factors including receptor agonists [44-48] and transcription factor
[49]
inducers . It is thought that microglial receptors [50-52] can act as molecular switches to control microglial
[53]
responses and that many of these actions function through alterations in calcium signals . In all cases, the
immediate response upon sensing DAMPs, PAMPs, or other damaging events requires a robust increase in
metabolic demand to support actions that initially are beneficial to the homeostatic balance of the nervous
system.

Injury-induced inflammatory processes are dynamic and demonstrate spatial and temporal heterogeneity [54-56] .
In general, characterization of the macrophage response is based on the nature of the activating stimulus
[57]
and the resulting production of factors . A conceptual framework has been proposed that suggests the
nature of the activating stimulus can drive a range of activation phenotypes [58-62] , and it has been used as a
basis for characterizing cellular responses [63-70] . While phenotypic activation-state distinctions are currently
under scrutiny [67,71] , it has been shown that classically activated microglia associated with inflammation can
be produced upon stimulation with agonists for toll-like receptors (e.g., lipopolysaccharide, LPS) or IFNg
receptors. In contrast, different aspects of the immune response that do not involve the classical response
can be observed upon stimulation by IL-4 or IL-13 with the expression of anti-inflammatory cytokines (IL-4,
IL-10, IL-13, and TGF-b), arginase-1 (Arg1), CD206, and Chitinase-3-like-3 (Ym1 in rodents) [72-76] . It is
considered that the different phenotypes may be related, yet have different roles in host defense, wound
healing, and resolution of inflammation [57,60] . Differences in metabolic processes have been identified across
these different activation inducers, suggesting a role for mitochondria in phenotypic outcome .
[77]