5 - Macrophages pt. 2 Flashcards
Immune response in inner ear
- inner ear believed to lack any active immune responses
Are any macrophages present in the ear?
Macrophages resident in stria vascular
What is the relationship between macrophages and hearing?
- macrophages are implicated in loss of hair cells
- understanding inflammation and resolution in the inner ear has implications for therapeutic measures such as cochlear implants
What did Liu et al do relating to macrophages and hearing?
- Study by Liu et al (2018: Front. Immunol. 9:223) identified population of ear macrophages using marker protein IBA1 (actin crosslinker in macrophages/microglia, associated with membranes and phagocytosis).
- Human cochlear samples collected during brain tumour surgery, with
patient consent and ethical approval - Inner ear section showing migratory Mφ (Ma) close to damaged hair cell (HC)
How did Liu et al analyse macrophages?
Human cochlear mφ analysed using marker protein IBA1 (actin crosslinker in macrophages/microglia associated with membranes and phagocytosis)
What did Liu et al find?
- Active macrophages found to migrate close to damaged hair cells.
- Results suggest that the human auditory nerve is under the
surveillance of resident and active tissue macrophages
- normal hair cell
- dying hair cell retracts below basal lamina
- activated macrophage removes dead cell
Macrophage interactions between hair cells and neurons
- Macrophages [ionized calcium-binding adaptor molecule 1 (IBA1) cells] can be observed in the human cochlea, both in the spiral ganglion and more seldom in the organ of corti.
- Macrophages may interact to form a protective link between hair cells and neurons via a fractalkine/CX3CR1 signaling system as demonstrated experimentally by Kaur et al
Liu et al, IBAs
- Confocal and Super-Resolution
- Structured Illumination Microscopy (CF, SR-SIM) showing association between
- IBA1 +ve cells and neurons
- IBA Mφs have distinctive appearance, including two long filopodia
What has experimental data suggest about macrophages in hair cells and neurons?
- Experimental data suggest that macrophages may interact and form protective links between hair cells and neurones
- Proposed link via a fractalkine/CX3CR1 signalling system
Macrophage changes after noise exposure (mice)
- control : macrophages at low numbers, dendritic phenotypes
- 7 days post noise : macrophage increased, amoeboid
Hair follicle cell cycle
- growth (anagen)
- regression (catagen)
- rest (telogen)
- anagen onset
- exogen
What does the anlagen stage of hair follicle cell cycle require?
- Entry into anagen requires activation of HF stem cells
- Skin Mφ numbers decrease before anagen onset
Immune system of hair follicles
HFs have a distinctive immune system - collapse results in inflammatory hair loss disorders
What is the hair follicle cycle controlled by?
HF cycle controlled by a stimulatory signalling pathway – Wnt (wingless/integrated) and inhibitory proteins BMPs (bone morphogenetic proteins)
What changes during the hair follicle cell cycle?
Immune cell populations (myeloid lines) fluctuate substantially (number and activity) during HF cycle, with subsequent changes in skin immune responses
What modulates hair follicle cycle?
Skin-resident mφ modulate HF cycle
What is associated with Ant signalling?
Reduction of skin macrophages via apoptotic death associated with activation of Wnt signalling
What was used to induce apoptosis in the Castellana et al. mouse model?
- Clodronate-encapsulated liposomes (CL-lipo) - specifically engulfed by macrophages, induce their apoptosis
- Premature appearance of hair coat in CL-lipo mice, compared with
controls
What contributed to the activation of epithelial HF-SCs in the mouse model?
Secretion of Wnt arising from apoptosis of perifollicular macrophages contributes to the activation of epithelial HF-SCs, allowing HF entry into anagen
What was established about HF-SCs?
Established elsewhere that HF-SCs contribute to wound healing, therefore further research on macrophages, anagen and wound healing suggested to improve understanding of skin inflammation and wound repair
Title of Wang et al. 2019 study
A Subset of TREM2+ Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth
What was found in the study by Wang et al., 2019
- JAK-STAT5 signalling maintains quiescence in HF stem cells
- The cytokine oncostatin M (OSM) acts upstream of JAK-STAT5 signalling to maintain HFSC quiescence
- Subset of TREM2+ macrophages in skin is the source of OSM
- Specific ablation of macrophages associated with anagen entry
What was found about TREM2+ cells in the Wang et al., 2019 study?
- Distinct subset of TREM2+ dermal macrophages identified, which secretes OSM, thus preventing HFSC proliferation and inhibiting hair growth
- TREM2+macrophages found to be genetically distinct and to share markers associated with microglia of the CNS
- TREM2+ cells spatially and temporally associated with early telogen HFs
- Macrophage depletion again associated with induction of hair growth in mice
- Name of ‘trichophages proposed to refer to the TREM2+ macrophages
Macrophages and melanin
- Skin macrophages have been observed which ingest melanin from neighbouring melanocytes – referred to as “melanophages”
- Using a mouse model, population of melanophages identified comprising major subset of dermal cells, previously overlooked
Macrophages and tattoo mouse doel
- Mouse model uses genetically modified mice in which human
diphtheria toxin receptor (hDTR) placed under control of specific gene promoter - Allows cell subsets of interest to be deleted from the animal
- Baranska et al (2018) used hDTR model that specifically ablated
macrophages, monocytes, and monocyte-derived cells in vivo. - Mouse model used to ablate dermal macrophages laden with green pigment particles and to determine whether their death results in tattoo disappearance
What are the two macrophage tattoo models?
- Pigment capture-release-recapture model
- The “longevity” model
Pigment capture-release-recapture model
- Dying dermal mφs continuously replaced
- On death, tattoo particles released and remain extracellularly at site, with subsequent recapture by incoming mφs
The “longevity” model
Possible that small number of dermal mφs including those with ingested tattoo pigments have similar longevity to adult mice
Characteristics of macrophages
Macrophages have high degree of plasticity, numerous phenotypes exist, broadly classified into M1, M2 and regulatory macrophages
Where were macrophages identified?
Macrophages now identified in the inner ear and found in association with hair cells
What is a subset of macrophages observed to associate with?
Distinct subset of macrophages seen to associate with nerve cells
What is macrophage apoptosis linked to?
Apoptosis of macrophages linked to stimulation of hair growth, linked to wnt, JAK-STAT signalling pathways and secretion of cytokine OSM
What is the reason for tattoo persistence?
Re-uptake of tattoo ink and longevity of skin macrophages believed to be responsible for tattoo persistence
