Dysregulation of miR-155-5p and miR-200-3p and the Anti-Non-Bilayer Phospholipid Arrangement Antibodies Favor the Development of Lupus in Three Novel Murine Lupus Models

Table 1

Relevant functions and effects of miRNAs previously described in human lupus and other autoimmune diseases, which were also found deregulated in the three murine lupus-like models.

Data from the three murine lupus-like models analyzed			Data from SLE and other autoimmune diseases
Deregulated miRNAs	Fold change		Targeted gene	Gene function	Possible effects
	mArray	RTPCR
▼ miR-155-5p	0.51	0.43	SFPI1 (SPI1)	Impairs class-switch DNA recombination and plasma cell differentiation.	Reduction of B cell activation [28].
			SHIP-1	Negative regulator of B cell activation.	Reduction of high-affinity IgG 1 antibodies [33].
			AICDA	Higher mutation frequency involved in somatic hypermutation.	B cell activation and production of high-affinity IgG 1 antibodies [34, 48].
			SMAD2/EP300^c	Transcription factor complex (TFC) triggered by TGF-β signaling.	TFC binding to IFNA1 and IFNA2 promoter due TGF-β activation [48–50].
			EED^c	Part of a transcription factor complex (TFC).	TFC binding to IFNA2 promoter [49, 50].
▼ miR-146b-5p	0.57	0.78	TRAF6, IRAK1	NF-κB activation.	Increase proinflammatory cytokines (IL-1, IL-6, IL-8, TNF-α, and IL-12) [51].
			STAT1, IRF5	Hyperactivation of type I interferon pathway.	Increase type I IFN (a hallmark of SLE) [52].
▼ miR-142a-3p; ▼ miR-142a-5p	0.51; 0.92	0.70^a	SAP, CD84, & LL-10	Increased SAP, CD84, and IL-10 protein levels.	CD4+ T cell overactivation and B cell hyperstimulation [53].
▼ miR-342-3p^b	−1.58	0.62	EP300, BMPR2, & PDGFRA	NF-κB activation.; Cytokine signaling.	Increase proinflammatory cytokines IL-1, IL-6, IL-8, and TNF-α (in type 1 diabetes mellitus) [14, 15].; (miRNA specifically decreased in SLE patients with active nephritis.)
▼ miR-200a-3p	9.25	6.58	SMAD2, GATA3, & FOXO3	JAK/STAT, TGF-β, and mTOR pathways.	Induced differentiation of Th17 cells and inhibited Treg or T helper pathways; (in multiple sclerosis) [36].
			EED & EZH2^c	Part of a transcription factor complex (TFC).	TFC binding to IFNA2 promoter [49, 50].
▲ miR-21a-5p	1.16	1.65	RASGRP1 & DNMT1	Underexpression of DNA methyltransferase (DNMT1).	Hypomethylation of DNA. A possible key event in the pathogenesis of SLE [54, 55].
▲ miR-125a-5p	2.90	1.34	KLF13	Reduction in the production of KLF13 and RANTES.	Reduction of the inflammatory chemokine RANTES levels [56].

Table 1 summarizes the data previously reported from SLE and multiple sclerosis patients for each miRNA. Direction of triangles indicates upregulation or downregulation (inverted) of miRNAs. ^aTaqMan probe-primers system used can identify both miRNAs. ^bmiRNA not included in the PCR array, but previously reported as important in lupus [14, 15]. ^cData obtained through analysis of miR-155-5p and miR-200a-3p signaling networks by Cytoscape [17] and the experimentally reviewed database from Cancer miRNA Regulating Network [18] (see Figure 4).