Anthrax Toxin Induces Macrophage Death by p38 MAPK Inhibition but Leads to Inflammasome Activation via ATP Leakage

Laboratory of Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
Immunity (Impact Factor: 21.56). 06/2011; 35(1):34-44. DOI: 10.1016/j.immuni.2011.04.015
Source: PubMed


Detection of microbial constituents by membrane associated and cytoplasmic pattern recognition receptors is the essence of innate immunity, leading to activation of protective host responses. However, it is still unclear how immune cells specifically respond to pathogenic bacteria. Using virulent and nonvirulent strains of Bacillus anthracis, we have shown that secretion of ATP by infected macrophages and the sequential activation of the P2X7 purinergic receptor and nucleotide binding oligomerization domain (NOD)-like receptors are critical for IL-1-dependent host protection from virulent B. anthracis. Importantly, lethal toxin produced by virulent B. anthracis blocked activation of protein kinases, p38 MAPK and AKT, resulting in opening of a connexin ATP release channel and induction of macrophage death. Prevention of cell death or ATP release through constitutive p38 or AKT activation interfered with inflammasome activation and IL-1β production, thereby compromising antimicrobial immunity.

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    • "Activation of NOD-like receptors (NLRs), Aim2, and RIG-I all trigger inflammasome activation upon sensing of bacterial flagellin, DNA, and RNA, respectively (Fig 2). Cytosolic presence of cathepsin B or ATP leakage, that indicates vesicle damage induced by phagocytosed bacteria, activates NLRP3 and NRLP1 inflammasomes (Duncan et al, 2009; Meixenberger et al, 2010; Ali et al, 2011). "
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    • "Cleavage by the anthrax toxin directly activates CARD, leading to activation of caspase-1 [13]. An alternative mechanism of NLRP1 activation is by the toxin inhibiting p38 mitogen-activated protein kinase and Akt kinase, leading to opening of the connexion channel for ATP release, resulting in P2X7R signaling [14]. There are similarities with the mechanism of activation of the NLRP3 inflammasome. "
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    • "In addition to its direct cardiovascular effects, LT may contribute to shock by promoting B. anthracis infection [44]. LT inactivates MAPKK pathways central to innate and adaptive immune responses and, therefore, may impair host defense and microbial clearance [22,25,45-47]. In one murine model, pretreatment with sublethal LT doses before intravenous E. coli challenge, increased blood bacterial counts and worsened survival [48]. "
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