The New Insight into the Role of Antimicrobial Proteins-Alarmins in the Immunopathogenesis of Psoriasis

Table 1

(a) Cathelicidin (LL-37)—the mechanisms of action in psoriasis. (b) S100 proteins—the mechanisms of action in psoriasis. (c) Human β-defensins—the mechanisms of action in psoriasis.

(a)

AMP	Abnormalities in psoriasis	Source	Target cells	Receptor	Mechanism of action in psoriasis pathohenesis
Cathelicidin (LL-37)	(i) Up-regulation; in psoriatic skin; lesions [10, 11]; *Specific processing; of precursor protein; LL-37 exclusively; detectable form; (ii) Elevated serum level	Mainly keratinocytes; and phagocytes; also T-cells, NK-cells,; monocytes, mast cells	Protein-nucleic acid binding phenomenon on early step of psoriasis pathogenesis
			^1pDCs	TLR-9	Self-DNA-LL-37 complexes activate and prime pDCs for production of INF-α by pDCs [9]
			^1pDCs	TLR-7	Self-RNA-LL-37 complexes activate and prime pDCs for production of INF-α [39]
			^2mDCs	TLR-8	Self-RNA-LL-37 complexes activate and prime mDCs for production of TNF-α, IL-6 and stimulate differentiation of mDCs into mature DCs [39]
			^3slanDCs	TLR-7, TLR-8, TLR-9	Self-RNA-LL-37 complexes activate slanDCs [40]
				TLR-7, TLR-8	Self-RNA-LL-37 complexes prime slanDCs for production of pro-inflammatory cytokines: TNF-α, IL-6, IL-12p70, IL-12/IL-23p40 through TLR7/8 [40]
			keratinocytes	TLR-9	LL-37 enhances TLR-9 expression by keratinocytes and responsiveness to self-DNA with subsequent production of type I IFNs [35]
					LL-37 acts synergisitically with IL-17 and IL-22 to prime keratinocytes for production of CXCL-8/IL-8 and IL-6 [36, 42]
			Monocytes	TLR-independent manner (mediated by ds-DNA)	LL-37 transports self-DNA into monocytes leading to the activation of these cells and production of IFN type I [41]
			Neutrophils	NADPH oxidase activation	Prime neutrophils for production of reactive oxygen species and human alpha-defensins [44]
	—		Monocytes/macrophages, T-cells, neutrophils, mast cells	^5FPRL-1	LL-37 acts as chemotactic factor [23, 24]
			Endothelial cells	^5FPRL-1	LL-37 promotes neovascularization by induction of the proliferation and migration of endothelial cells and formation of tube-like structures [46]

1pDCs: plasmacytoid dendritic cells; ²mDCs: myeloid dendritic cells; ³slanDC: 6-sulfoLacNAc dendritic cells; ⁴TLRs: toll-like receptors; ⁵formyl-peptide receptor-like 1 (FPRL-1).

(b)

AMP	Abnormalities in psoriasis	Source	Receptor	Target cells	Mechanism of action in psoriasis pathohenesis
Psoriasin (S100A7)	Up-regulation in psoriatic skin lesions; expression in epidermal suprabasal compartment [13, 59]	Mainly keratinocytes and phagocytes	^1RAGE	Monocytes,; neutrophils; lymphocytes	Chemoattractant [60]
				Keratinocytes	Alarmin, prime keratinocytes for enhanced production of pro-inflammatory cytokines: TNF-α, IL-6, IL-8 [62].
				Neutrophils	Alarmin, prime neutrophils for production of pro-inflammatory cytokines and chemokines, including: IL-6, IL-8, TNF-α, ^2MIP-1α, ^3MIP-1β and reactive oxygen species [57]
				Endothelial cells	Induction of angiogenesis [63]
Koebnerisin (S100A15)	(i) Up-regulation in psoriatic skin lesions; (ii) Expression in epidermal suprabasal compartment, basal keratinocytes, melanocytes, Langerhans cells, dendritic cells, smooth muscle cells and endothelium of blood vessels [14, 59]	Mainly keratinocytes but possibly also other cells	^4GiPCR	Monocytes,; neutrophils	Chemoattractant [60]
				Keratinocytes	Alarmin, prime keratinocytes for enhanced production of pro-inflammatory cytokines: TNF-α, IL-6, IL-8 [62].
Calgranulin A/calgranulin B (S100A8/S100A9)	Up-regulation in psoriatic skin lesions [70, 71]	Phagocytes,; psoriatic keratinocytes, endothelial cells, vascular muscle cells	^1RAGE	Keratinocytes	(i) Alarmin, prime keratinocytes for enhanced production of pro-inflammatory and pro-angiogenic cytokines, such as: IL-6, IL-8, and TNF-α, ^5GROs; (ii) Stimulation of proliferation [68, 71]
				Immune cells; (monocytes/macrophages, lymphocytes)	Chemoattractant [71]
				Endothelial cells	Induction of angiogenesis [71]
Calgranulin C (S100A12)	Up-regulation in psoriatic skin lesions [73]		^1RAGE

1RAGE: multiligand receptor for advanced glycated end products; ²MIP-1α: macrophage inflammatory protein-1α; ³MIP-1β: macrophage inflammatory protein-1β; ⁴Gi-protein-coupled receptor (GiPCR); ⁵GROs: growth-related gene product.

(c)

AMP	Abnormalities in psoriasis	Source		Receptor	Target cells	Mechanism of action in psoriasis pathogenesis
Human β-defensins 1, 2, 3 and 4 (HBD1–4)	Up-regulation in psoriatic skin lesions	Keratinocytes and phagocytes	HBD1–3	^1GiPCR	Memory T-cells, dendritic cells	Chemoattractant [23]
			HBD2	^1GiPCR	Neutrophils mast cells
			HBD3-4	^1GiPCR	Monocytes/macrophages
			HBD2–4	^1GiPCR,; ^2PLC	Keratinocytes	Alarmin, prime keratinocytes for enhanced production of pro-inflammatory cytokines and chemokines, including: IL-6, IL-10, ^3MCP-1, ^4MIP-3α, ^5RANTES, ^6IP-10 [83]
				^7EGFR-,; ^8STAT1-; ^9STAT3-mediated		Stimulate proliferation and migration [83]
			HBD2	TLR4	Immature dendritic cells	Stimulation, induction of Th1-mediated response [86]
			HBD3-4	TLR-9	pDCS	Activation and production of IFNs [87]
			HBD3-4	^10MAPK p38-and; ^11ERK1/2-mediated	Mast cells	Degranulation of mast cells, production of prostaglandin D2; increase mast cell-mediated vascular permeability in skin [76] production of pruritogenic cytokines-IL-31 [85].

1GiPCR: Gi-protein-coupled receptor; ²phospholipase C (PLC); ³MCP-1: monocyte chemoattractant protein-1; ⁴MIP-3α: macrophage inflammatory protein-3α; ⁵RANTES: regulated upon activation normal T cell expressed and secreted; ⁶IP-10: interferon-gamma-inducible protein-10; ⁷EGFR: epidermal growth factor receptor; ⁸STAT1: signal transducer and activator of transcription 1; ⁹STAT3: signal transducer and activator of transcription 3; ¹⁰MAPKp38: p38 mitogen-activated protein kinases; ¹¹ERKs; extracellular-signal-regulated kinases.