| Health | PD pathophysiology | |||||
|---|---|---|---|---|---|---|
| Type of microglia | Homeostatic | Amoeboid | Stress-primed | Hyper-ramified | Dark | Dystrophic |
| Morphology | Ramified Dynamic processes | Short and thick processes Rounded shape | Hyper-ramified Longer processes | Hyper-ramified Longer processes | Hyper-ramified Extremely thin processes | Short and twisted processes Spheroid swellings Fragmentation Phagocytic inclusions |
| Functions | Surveillance Inflammation Phagocytosis Self-renewal | ↑ Inflammation ↑ Motility ↑ Phagocytosis | ↔ Inflammation ↑ Reactivity to immune challenges | ↔ Inflammation ↑ Reactivity to immune challenges | ↑ Interactions with synapses ↑ Markers of oxidative stress | ↓ Surveillance ↓ Phagocytosis ↑ Inflammation ↑ Markers of oxidative stress |
| at resting state | Reactive (Activated) | ||
|---|---|---|---|
| a quiescent ramified form | Bushy, rods an amoeboid form | ||
| do not phagocytose cells and secrete fewer immunomolecules (including the MHC class I/II proteins). | activated but non-phagocytic | ||
| M1 | M2 | ||
| function |
pro-inflammatory Left + phagocytic! Antigen presenting, (uptake of MHC class I/II proteins), expression of immunomolecules, secretion of cytotoxic factors, secretion of recruitment molecules, and secretion of pro-inflammatory signaling molecules (resulting in a pro-inflammation signal cascade). But non-phagocytic | anti-inflammatory | |
| marker |
MPTP administration leads to the activation of microglia toward M1 phenotype in mice (Pisanu et al., 2014). Iba1 led to increased death of DA neurons in vitro, (Tang et al., 2014). | whereas addition of M2 microglia reversed the neurotoxicity | |
| (Alekseeva, 2019 #1262) an inactive state is under control of some neuronal factors, including CD200 and fractalkine (CX3CL1) [39]. CD200 is a glycoprotein, which is expressed on neuronal membranes. Its receptor, CD200R, sits on membranes of microglial cells [40, 41]. | (Alekseeva, 2019 #1262) When ramified microglia are transformed into amoeboid one, the cell size increases due to increased volume of the perinuclear cytoplasm. While doing this, the processes become shorter and thicker. The cytoplasm begins to abound in lysosomes, while the Golgi complex undergoes hypertrophy. In the cytoplasm of phagocyting microglia, multiple phagosomes emerge. | ||
Markers of microglia
Good source: (Jurga, 2020 #2031)
| IBA1 | CD68 | HLA-DR (MHCII) | TMEM119 | CD11b and CD45 | CX3CR1 | F4/80 | CD40 | |
|---|---|---|---|---|---|---|---|---|
| location | cytoplasm | a lysosomal protein | Cell surface | Cell surface | Cell surface | Cell surface | ||
| Cell type | microglial and macrophage | macrophages and microglia | (In humans, there are three MHC class II isotypes: HLA-DR, HLA-DP, and HLA-DQ, encoded by α and β chain genes within the Human Leukocyte Antigen (HLA) locus on chromosome 6) | it isn't expressed by macrophages or other immune or neural cell types. | A combination of CD11b and CD45 labeling can be used to distinguish microglia from macrophages. | microglia and macrophages | macrophages and resting microglia. | macrophages and microglia |
| species | Human & mouse | |||||||
| Microglia: resting vs reactive |
involved with phagocytosis in activated microglia. (Hendricks 2017) Iba1 is probably the first marker to be upregulated during early immune activation. Iba1 was scarcely expressed by ramified microglia in control tissue, while HLA-DR and CD68 were still moderately expressed. |
activated microglia and in low levels by resting microglia. (Hendricks 2017) CD68, although widely expressed in different activation stages, is least useful to study morphology (and thus phenotype) due to its intracellular expression because In ramified and amoeboid microglia, these lysosomes are mainly located near the nucleus, and the typical extrusions can therefore not be observed with CD68 staining. | Resting microglia are CD11bhi, CD45low, whereas macrophages are CD11bhi, CD45hi. | resting microglia. | Activated microglia | |||
| Cell body morphology 분석에 적합. | Cell body 보이므로 morphology 분석에 적합. | (Hendricks 2017) AD에 더 적합, Microglia accumulations associated with dense-core AD plaques expressed mostly HLA-DR | ||||||
| Hendricks 2017) HLA-DR, CD68 and Iba1 are expressed by all the different microglia phenotypes (ie resting to amoeboid), but, Iba1 was scarcely expressed by ramified microglia in control tissue, while HLA-DR and CD68 were still moderately expressed. | ||||||||
MHC:
- cell surface proteins
- normal human body
- In a cell, protein molecules of the host’s own phenotype are continually synthesized and degraded. → Each MHC molecule on the cell surface displays a small peptide (a molecular fraction of a protein) called an epitope.[3] → The presented self-antigens prevent an organism’s immune system from targeting its own cells.
- normal human brain
- samples reported MHC class II expression primarily by perivascular MPS cells and white matter microglial cells.
- neuropathologic disorders
- Marked increases in MHC class II-expressing microglia have been shown in many neuropathologic disorders, including Alzheimer’s disease (AD).
- There are two antibodies against MHC class II (HLA-DR; LN3),
| MHC Class I | MHC Class II | MHC Class III | |
|---|---|---|---|
| expressed in | all nucleated cells and also in platelets—in essence all cells but red blood cells. | only on "professional" antigen-presenting cells (APCs): macrophages, B cells, and especially dendritic cells (DCs). | |
| It presents epitopes to | killer T cells, also called cytotoxic T lymphocytes (CTLs). | CD4+ (helper) T cell, Treg cells | |
| comprises | HLA-A, HLA-B, and HLA-C molecules | ||
| If increased | Increased MHC-II is often concurrently upregulated with genes for proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 β (IL-1β) [13]. | ||
| If decreased | decreased MHC-II expression was shown to attenuate downstream secretion of proinflammatory cytokines [14,15]. |
Priming of MG
- definition of “priming”
- microglia will respond more aggressively and more easily to activating factors
- the microglial cells will be activated in a much stronger state one step further in activation.
- Primed microglia are more sensitive to second stimulating factors and have a much stronger potential for reacting to the stimulating factors and even normal cells.
- model
- (2013 Lundbeck) priming signal → resulting in the transcription of pro-IL1β, LPS/TLR4
Receptors on microglia
| Receptors for | ligand | |
|---|---|---|
| (TREM2), triggering receptor expressed on myeloid cells 2 and | ||
| the receptor for colony stimulating factor 1 (Csfr1), | ||
| purinergic receptors | ionotropic (P2X4 and P2X7) | ATP released from neurons in the brain parenchyma after nerve injury. |
| metabotropic (P2Y1, P2Y2, and P2Y12) | Same as above? | |
| major histocompatibility complex | ||
| complement receptors |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
Type of microglia top-table / Morphology and Functions descriptors | the descriptors are pulled from the labels printed under each silhouette in the figure row; the column for Stress-primed and Hyper-ramified reuse Hyper-ramified / Longer processes because the printed labels under both columns appear identical in the available crop. | low confidence on whether the printed labels for Stress-primed and Hyper-ramified are truly identical in the source. |
Markers / Cell body morphology row first cell | the IBA1 column entry for the Cell body morphology row is preserved as Cell body morphology 분석에 적합.; the leading Cell body 보이므로 Korean annotation is captured under the CD68 column based on visible cell boundaries in body_r03_c01.jpg. | low confidence on which column the Korean annotation belongs to. |
Receptors on microglia / second column | the second column header appears blank in the captured frame and only the ionotropic and metabotropic purinergic sub-rows are populated. | low confidence on whether the second column is empty by design or merely clipped. |