Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain

Abstract

Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. The extracellular release of Prxs in the ischemic core occurred 12 h after stroke onset, and neutralization of extracellular Prxs with antibodies suppressed inflammatory cytokine expression and infarct volume growth. In contrast, high mobility group box 1 (HMGB1), a well-known damage-associated molecular pattern molecule, was released before Prx and had a limited role in post-ischemic macrophage activation. We thus propose that extracellular Prxs are previously unknown danger signals in the ischemic brain and that its blocking agents are potent neuroprotective tools.

Cysteine Oxidation Targets Peroxiredoxins 1 and 2 for Exosomal Release through a Novel Mechanism of Redox-Dependent Secretion

“…The redox regulation of these Prdxs is of particular importance as the proinflammatory activity of both Prdx1 (11,12) and Prdx2 (10,13) has been demonstrated previously. The fact that these Prdxs are released in a redox-regulated manner in response to inflammatory stimuli as well as oxidant treatment is the first evidence for the potential generation of inflammatory mediators by cellular redox changes.…”

“…The released Prdx2 then acts to induce production of inflammatory cytokines, like a classical inflammatory danger signal (11). Studies by others also have shown that Prdx1, 5 and 6 also induce inflammatory cytokines in vitro (12,13).…”

Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

“…43,44 The extracellular release of HMGB1 is substantially increased during retinal degeneration after retinal detachment, 45 as well as dsRNA-induced retinal injury. Besides HMGB1, Shichita et al 46 recently reported that other DAMPs such as extracellular peroxiredoxin family proteins mediate postischemic inflammation in the brain. In other studies, it was shown that damaged mitochondria released from necrotic cells are critical for inflammatory responses to tissue injury.…”

Peroxiredoxin 1 Contributes to Host Defenses against Mycobacterium tuberculosis

“…4E). A number of studies, however, demonstrated that recombinant human PRDX1 bound to TLR4 and stimulated Mfs or DCs to produce inflammatory cytokines (22,23). The production was dependent on the TLR4-MyD88 signaling pathway, which results in activation of NF-kB (23).…”

“…In the case of brain stroke, which causes ischemia-reperfusion injury, PRDX1 released from necrotic cells worsened the brain damage via initiating inflammation (22). Recombinant PRDX1 binds TLR4 and positively regulates inflammation (22)(23)(24).…”