Danger signals in stroke and their role on microglia activation after ischemia

Abstract

Ischemic stroke is a major cause of death. Besides the direct damage resulting from oxygen and glucose deprivation, sterile inflammation plays a pivotal role in increasing cellular death. Damaged-associated molecular patterns (DAMPs) are passively released from dying cells and activate the innate immune system. Thus, they take part in the direct and rapid activation of the inflammatory response after stroke onset. In this review the role of the most important DAMPs, high mobility group box 1, heat and cold shock proteins, purines, and peroxiredoxins, are addressed. Moreover, intracellular pathways activated by DAMPs in microglia are illuminated.

Keywords: DAMPs; HMGB1; Hsp; microglia; peroxiredoxin; purines; stroke.

Figure 1.

DAMP associated pathways in microglia. (a) Glucocorticoids (GCs) induce the production of the disulfide form of high mobility group box 1 (dsHMGB1), which secondarily binds to its pattern recognition receptor (PRR). Nuclear factor κB (NFκB) is activated, translocates to the nucleus and nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) components are transcribed as well as pro-interleukin-1β (pro-IL-1β). A second immune challenge results in higher levels of oligomerized NLRP3. The core structures of the NLRP3 inflammasome are the NOD-like receptor NALP3, the adaptor of the apoptosis associated speck-like protein (ASC) with a caspase recruitment domain (CARD) and the protein caspase 1. When an activating signal is sensed, the oligomerization of the inflammasome starts, which leads to the proteolytic cleavage of pro-IL-1β into the bioactive mature IL-1β through caspase 1 and thus, a potentiated inflammatory response. The described pathways are best demonstrated by toll-like receptor (TLR)-agonist lipopolysaccharide (LPS). (b) Heat shock protein (Hsp) binds to its TLR4 receptors and Hsp70 associates with Na+/H+ exchanger 1 (NHE1). Ca²⁺ streams into the cell activating both Ca^2+-cal-modulin-dependent protein kinase II (CaMKII) and transforming growth factor β-activated kinase 1 (TAK1). IκB kinase β (IKKβ) initiates the degradation of Inhibitors-of-kappaBand liberates NFκB, resulting in a higher gene transcription of inducible nitric oxide synthase (iNOS) and other proinflammatory cytokines. Hsp also upregulates hypoxia inducible factor 1 (HIF-1), interferon regulator factor 1 (IFR1) and single transducer and activator of transcription 3 (STAT3) through TLR2 and -4. The described pathways are best demonstrated by TLR agonist LPS.

Figure 2.

Peroxiredoxin-associated pathways in microglia. Damaged-associated molecular patterns (DAMPs) such as peroxiredoxin family proteins Prx-1, -2 and -4 activate the the Nox (membranous NADPH oxidase) /ROS (reactive oxygen species)/ JNK (c-jun N-terminal kinase) axis and the concentrations of Nuclear-Factor κB (NFκB), mitogen-activated protein kinase (P38/MAPK) and reactive oxygen species (ROS) increase. Both Prx-1 and Prx-5 are upregulated and diminish the proinflammatory response by lowering ROS and NFκB signaling. Described pathways are best demonstrated by toll-like receptor (TLR) agonist lipopolysaccharide (LPS).

Figure 3.

Nucleotide-associated pathways in microglia. A toll-like receptor (TLR) agonist such as lipopolysaccharide (LPS) leads to the release of proinflammatory mediators such as interleukin (IL)-6 in an ATP-dependent manner. Signaling through P2X4 receptors enhances migration of microglia. Uridine triphosphate (UTP) binds to P2Y2/4, Uridine diphosphate (UDP) to P2Y6 and adenosine diphosphate (ADP) to P2Y12, which results in a higher rate of phagocytosis. 2’,3’-cyclic adenosine monophosphate (cAMP) is released from damaged cells and is metabolized by an extracellular pathway to 2’- and 3’-adenosine monophosphate (AMP), which is then metabolized to adenosine. After adenosine has activated its A1 receptor, it possesses neuroprotective functions.