Dendritic cells and the extracellular matrix: A challenge for maintaining tolerance/homeostasis

Table 1 Dendritic cells and the maintenance of homeostasis in different tissues

Tissue	Location	Resident DC in naïve tissue	Resident associated cells/naïve tissue	Stromal/cellular interactions in immune homeostasis	Ref.
Skin	Epidermis	Cd1a+ Langerin+ Langerhans cells expressing Birbeck granules	Keratinocytes	E-cadherin junctions with keratinocytes, TGF-β production, tolerogenic Treg responses	[6, 40-42]
	Dermis	CD1c+ DC-SIGN+ DEC205+ dermal DC subsets (Langerin+ CD11blow, Langerin-CD11b-, and Langerin-CD11blow)	To be elucidated (presumed dermal matrix, fibroblasts)	Pluripotent dermal DC may present antigen, migrate or reside in tissue depending on local interactions	[69, 144]
Intestinal mucosa	LP, Peyer’s patches, GALT, SILT	CD103+CD11b+ or CD103+ CD11b-migratory DC, CD103+Sirpα- DC, pDC, CX3CR1+ DC	Macrophages, B cells	Maintain immune homeostasis, induce Treg differentiation, oral tolerance (TGF-β, Treg, TH2 factors)	[5, 48-50, 145, 146]
				Gut: Retinoic acid, TH17 cells
				LP: indoleamine 2,3-dioxygenase
				CD83 on DC regulates mucosal tolerance
Liver	Portal tracts, interstitial DC	CD103+DC, CD103-DC, CD103-CD11b+DC, CD141+ DC (high in healthy liver)	Hepatic stellate cells, sinusoidal endothelial cells, Kupffer cells, hepatocytes	Inhibit DC activation (indoleamine-2,3-dioxygenase expression), repress T cell activation (IL-10, TGF-β) via CTLA-4, PD-1	[4, 51, 52,147,148]
Cornea	Central/peripheral corneal stroma	CD11b+ CD11c+ DC, B220+ CD11clo pDC, CD34+ MHCII myeloid precursors	Stromal Collagen I, CD11b+ CD11c- macrophages, keratocytes	Maintain MHCIIlow CD80low CD86low phenotype under normal conditions	[54-57]
Spleen	Marginal zones	Lymphoid, myeloid and pDC	Macrophages, T cells, B cells (zone dependant)	To be elucidated	[58-60]
Bone marrow	Osteoblastic or vascular niches	Resident hematopoietic stem cell DC progenitors	Osteoblasts, stromal cells and sinusoidal endothelial cells	-	[61]
Retina	Peripheral margins and juxtapapillary areas	Presence of DCs is debated.	Likely migrated in from choroid, ciliary body and meninges	Perivasulcar - around retinal venules (initial site of immune disruption), but not arterioles.	[149]
		Few MHCII+ 33D1+ DC observed in naïve brain
Brain	Regions of synaptic plasticity and neurogenesis	Presence of DCs is debated.	-	-	[62,63,150]
		Brain-derived CD11c+ DC
Bone/cartilage/vitreous	Not detected	-	-	-	-

DC: Dendritic cell; TGF-β: Transforming growth factor-β; LP: Lamina propria; GALT: Gut-associated lymphoid tissues; SILT: Solitary intestinal lymphoid tissue; MHCII: Major histocompatibility complex class II; IL: Interleukin-4.

Table 2 Dendritic cell interactions with extracellular matrix components

Class of component	ECM component	DC responses	DC receptors	Overall impact
Collagen	Soluble collagen I[74]	Murine BMDC upregulated CD86, IL-12, antigen uptake	DDR2	Pro-inflammatory
	Soluble collagen I[75]	Human MDDC increased IL-12p40, TNF-α, IFN-γ	DDR2	Pro-inflammatory
	Adsorbed collagen I, II, III[76]	Human MDDC increased maturation markers, pro-inflammatory cytokines, allostimulation	OSCAR	Pro-inflammatory
	Dermal hydrogel (laminin β3, collagen IV, VII)[77]	Decreased width of granulation tissue	-	Skin regeneration, anti-infl.
	Adsorbed fibronectin, collagen I, gelatin, Matrigel[78]	Murine myeloid DC on Matrigel were less mature (maturation marker, cytokines, morphology)	Adhesion complexes (CD29, CD49a-f, CD41, CD51, CD61)	Differential effects – Matrigel less inflammatory vs collagen I
	Collagen-like motifs in complement C1q[124]	Inhibits MDDC differentiation, TLR activity of pDC	LAIR-1	Anti-inflammatory
Glycoproteins	Pre-adsorbed laminin, fibronectin[79]	Human MDDC remained immature (maturation marker, high endocytosis)	Mannose receptor, DC-SIGN	Anti-inflammatory
	Modified Arg-Gly-Asp (RGD) on fibrillin[80]	Murine pDC adherence, TGB-β secretion increased in systemic sclerosis model	Integrins	Pro-fibrotic
Proteoglycans	Heparan sulfate[113,119]	DC maturation increased (morphology, costimulatory factors, T cell stimulation)	TLR4	Pro-inflammatory
		In GVHD blocking HS with alpha-1-antitrypsin limited alloreactive T cells	-	Pro-inflammatory
	Chondroitin sulfate[121]	Impact immunity in CNS pathologies	-	Pro- and anti-inflammatory
	DAMPs[111-113,117,118]	Activate DC	TLRs	Pro-infl.
Non-proteoglycan polysaccharides	Hyaluronan[82]	Increased hylauronan corresponds to decreased murine DC activation	-	Anti-inflammatory (tumours)
	Natural polymer hyaluronic acid[129,130]	Decreased DC maturation (maturation markers, cytokines, allostimulation)	-	Anti-inflammatory
Modulators	Secreted protein acidic and rich in cysteine[88]	Organization of germinal centres in LNs for TH17 by follicular DC	-	-
	Thrombospondin-1[89]	DC-derived thrombospondin inhibits resolution of inflammation	CD47, CD36	Anti-inflammatory
Enzymes	Matrix metalloproteinases[90]	Endogenous MMP-2 prime DC to TH2 (IL-12p70)	-	TH2 profile
	Tissue transglutaminases[151]	Influence DC activation (concentration-dependant)	-	Pro- and anti-inflammatory
Glycosylation modifications	Gut mucous[107]	Decrease in DC activation by inhibition of NF-κB	Dectin-1, galectin-3	Anti-inflammatory
	Tissue matrix in skin thymus, trachea[109]	Steady state homeostasis	MGL1+ MGL2+	Anti-inflammatory

DC: Dendritic cell; ECM: Extracellular matrix; OSCAR: Osteoclast-associated receptor; DDR: Discoidin domain receptors; IL: Interleukin-4; TNF-α: Tumour necrosis factor-α; IFN-γ: Interferon-γ; LAIR-1: Leukocyte-associated Ig-like receptor 1; TLR: Toll-like receptor; MGL: Macrophage galactose/N-acetylgalactosamine-specific C-type lectin.