Regulation of TREM2 expression by an NF-кB-sensitive miRNA-34a

Abstract

Genetic deficits and loss of function for the triggering receptor expressed in myeloid cells 2 (TREM2; encoded at chr6p21.1), a transmembrane spanning stimulatory receptor of the immunoglobulin/lectin-like gene superfamily, have been associated with deficiencies in phagocytosis and the innate immune system in Alzheimer’s disease. In this study, we provide evidence that TREM2 is downregulated in samples of sporadic Alzheimer hippocampal CA1 compared with age-matched controls. A nuclear factor-κB (NF-κB)-sensitive miRNA-34a (encoded at chr1p36.22), upregulated in Alzheimer’s disease, was found to target the 299 nucleotide human TREM2 mRNA 3′-untranslated region (3′-UTR) and downregulate the expression of a TREM2-3′-UTR reporter vector. A stabilized anti-miRNA-34a (AM-34a) quenched this pathogenic response. The results suggest that an epigenetic mechanism involving an NF-κB-mediated, miRNA-34a-regulated downregulation of TREM2 expression may shape innate immune and phagocytic responses that contribute to inflammatory neurodegeneration.

TREM2, Microglia, and Neurodegenerative Diseases

“…One mechanism by which the downregulation of TREM2 mRNA is proposed to occur is through the NF-kB pathway. Expression of microRNA miR-34a -which binds to the 3 0 untranslated region of TREM2 mRNA and downregulates its expression -is NFkB-dependent and is reportedly elevated in the brains of AD patients [99]. Interestingly, elevated miR-34a has also been detected in retinal samples from patients with age-related macular degeneration (AMD), a neurodegenerative disease in which photoreceptors, specialized neurons in the retina, are lost [100].…”

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

“…Apart from miRNA-146a, miRNA-34a might be related to AD development by upregulating neuroinflammation in the brain (Zhao et al 2013). MiRNA-34a is a NF-jBsensitive miRNA and reduces TREM2 expression, resulting in increased immune response and decreased phagocytic responses (Bhattacharjee et al 2014).…”

Sirtuin 1: A Target for Kidney Diseases

“…On the contrary, there was also evidence indicating that NF-κB inhibited SIRT1 expression and signaling. Reportedly, NF-κB could increase the expression of microRNA-34a (miR-34a), which targeted the 3′UTR of SIRT1 and inhibited SIRT1 expression (138)(139)(140)(141). SIRT1 even became cleaved in inflammatory status (78,79).…”