Kůže a lymfatický systém
HDL
- Particles as large as HDLs require transport through lymphatics to return to the bloodstream during reverse cholesterol transport
Dermal LVs
- Main conduits for pathogens and immune cells from the periphery to draining LNs
- Major role in reverse cholesterol transport
- By transporting high-density lipoprotein-bound cholesterol from peripheral tissues to systemic blood circulation
- To regulate cholesterol metabolism (Fig.?1?B; Lim et al., 2013; Martel et al., 2013; Randolph and Miller, 2014) [35]
- The migration rate of dendritic cells (DCs) and T lymphocytes via dermal aferent LVs is dramatically increased during the peak of inflammation (Fig.?1? C; Kim et al., 2014; Hunter et al., 2016) [35]
- The majority of immune cells in the lymph of afferent LVs
- T cells (80–90%)
- CD4+ T efector memory cells
- Main subset
- Foxp3+CD4+ regulatory T cells (T reg cells) - up to 25% of the intralymphatic T cell population (Brinkman et al., 2016; Hunter et al., 2016).
- DCs (10–15%; Hunter et al., 2016) [35]
- Tissue T reg cells
- Important regulators of dermal lymphatic function and repair LVs in inflammation and lymphedema (Gousopoulos et al., 2016) [35]
- C-C motif chemokine ligand 21 (CCL21) produced by LECs
- Required for DC and T cell traficking in skin LVs
- Likely in most LVs of other organs (Girard et al., 2012; Randolph et al., 2017) [35]
- LECs secrete CCL21 abluminally and luminally
- Extracellular CCL21 gradients guide both recruitment and intraluminal directional crawling of DCs (Russo et al., 2016; Randolph et al., 2017) [35]
- Sphingosine-1 phosphate (S1P)
- Signaling via S1P receptor 1 (S1PR1)
- Regulates a T cell’s decision to egress or remain in tissue (Baeyens et al., 2015) [35]
- Vascular cell adhesion molecule 1 (VCAM-1)
- Expressed by inflamed LECs
- Promotes T cell and DC entry into LVs (Brinkman et al., 2016; Randolph et al., 2017; Teijeira et al., 2017) [35]
- T reg cells produce especially high levels of lymphotoxin-alpha2beta1
- Engages lymphotoxin receptor-beta on LECs
- To promote cell transmigration (Brinkman et al., 2016) [35]
- Subsequent intralymphatic T cell adhesion and crawling within capillaries
- Supported by
- Intercellular adhesion molecule 1 (ICAM-1) on LECs
- Integrin lymphocyte function-associated antigen-1 on T cells (Teijeira et al., 2017) [35]
- C-X3-C motif chemokine ligand 1 and C-X-C motif chemokine ligand 12
- Secreted from LECs
- To guide DC and other innate immune cells traficking into inflamed LVs (Fig.?1?C; Kabashima et al., 2007; Johnson and Jackson, 2013) [35]
- Spectrum of chemokines and adhesion receptors produced by dermal LECs
- Difer depending on the nature of inflammatory stimuli [35]
- ICAM-1, CXCL9, and CXCL10
- Strongly induced in LECs in a contact hypersensitivity model
- Not during innate immune response elicited by complete Freund’s adjuvant [35]
- Skin LVs are organized in super?cial and deep lymphatic plexuses
- Superfcial LVs
- Are mostly capillaries
- Deep lymphatic plexus
- Contain collecting LVs
- Draining to the regional LNs [35]
- Main immune populations traffcking via dermal LVs in response to CCL21 gradient produced by capillary LECs
- CCR7+ CD4+ T cells,
- Langerhans cells (specialized skin DCs residing in epidermis)
- DCs [35]
- Dermal macrophages
- Sense tissue osmotic pressure
- Maintain tissue fluid homeostasis
- Maintain systemic blood pressure by
- Activating transcription factor NFAT5
- Producing VEGF-C
- Induces expansion of dermal LVs
- Enhances tissue clearance [35]
- DLEC, dermal LEC
- Inflamed LECs produce adhesion receptors
- VCAM-1 and ICAM-1, and chemokines (e.g., CXCL12)
- Enhance the attraction, adhesion, and intralymphatic crawling of immune cells [35]
- Lymphatic capillary hyaluronan receptor LYVE1
- Mediates interaction of
- LECs with hyaluronan-coated DCs + hyaluronan-containing capsule of some skin bacterial pathogens [35]
- LYVE1 in DC transmigration has been uncovered (Johnson et al., 2017) [35]
- Inflamed dermal interstitium
- DCs are coated with hyaluronan
- Interact with LYVE1 on lymphatic capillary LECs
- Mediating docking between the two cells within discrete “transmigratory cups”
- That envelop transiting DCs facilitate DC transmigration into LVs (Johnson et al., 2017) [35]
- Bacterial hyaluronic acid capsule
- Interaction with LEC LYVE1 involved in the spread of a common skin-resident pathogen
- Group A streptococcus (GAS) from the infection site to the regional draining LN ( Lynskey et al., 2015)
- Causes lymphangitis and lymphadenitis [35]
- Blocking LN accumulation of GAS in Lyve1 -/- mice
- Increased systemic dissemination of bacteria in blood circulation (Lynskey et al., 2015)
- High levels LYVE1 on LECs may be important for pathogen containment [35]
- Neutrophils are the 1st to migrate from inflamed skin to draining LN
- Stimulate lymphocyte proliferation (Hampton et al., 2015) [35]
- Neutrophil migration
- Relies on lymphocyte function–associated antigen 1
- Integrin/complement receptor CD11b
- C-X-C or C-C chemokine receptors CXCR4
- And/or CCR7 (Gorlino et al., 2014; Hampton et al., 2015; Arokiasamy et al., 2017) [35]
- Dermis also contains an abundant population of macrophages contributes to
- Local control of lymphangiogenesis
- Lymphatic remodeling during development, in?ammation, and wound healing (Harvey and Gordon, 2012; Kim et al., 2014) [35]
- In adult skin - macrophages
- Unique role in the regulation of salt-sensitive hypertension
- Response to increased local osmotic stress skin macrophages activate:
- Nuclear factor of activated T cell 5– dependent production
- Secretion of VEGF-C [35]
- Expansion of cutaneous lymphatic network enhances interstitial electrolyte clearance, reduces peripheral tissue ?uid pressure, and restores homeostasis (Machnik et al., 2010; Wiig et al., 2013) [35]
Lymfangiogeneze v kůži
- In skin, cervical and thoracic LVs
- Formed by lymphangiogenic sprouting of Tie2-lineage+ venous-derived LEC progenitors (Martinez-Corral et al., 2015) [35]
