ID: 123: PLZF restrains inflammation

Abstract

Inflammation is critical for host defence, but needs to be carefully controlled to avoid chronic disease or fatal responses. We have shown (Sadler et al. PNAS, 2015) that the BTB/POZ, zinc finger transcriptional regulator PLZF restricts the expression of inflammatory gene products. In accord with this, PLZF-deficient animals mount exaggerated inflammatory responses to infectious stimuli. This protective effect of PLZF is mediated via modulation of macrophage activity and there is increased inflammatory gene induction in the absence of PLZF. By analyzing genome-wide histone modifications we have discovered that PLZF establishes basal activity states of early response genes to maintain immune homeostasis and limit damaging inflammation. PLZF stabilizes a co-repressor complex that encompasses histone deacetylase activity to control chromatin. Further investigation of signaling from Toll-like receptors revealed calcium/calmodulin-dependent protein kinase (CaMK2) activates histone acetyltransferase-1 (HAT1), which then acetylates PLZF. Acetylation of PLZF promotes the assembly of a repressor complex incorporating HDAC3 and the NF- κ B p50 subunit that limits the NF- κ B response (Sadler et al. Nature Commun, 2015). Accordingly, diminishing the activity of CaMK2, the expression levels of PLZF or HAT1, or mutating key residues that are covalently modified in PLZF and HAT1, curtails control of the production of inflammatory cytokines. As we have previously shown that PLZF promotes the antiviral response (Xu et al., Immunity 2009), taken together these results suggest a strategy that could fullfil one of the major goals of immune therapy to retain immune resistance to pathogens while curbing damaging inflammation.