Pattern Recognition Receptors (PRRs) are proteins capable of recognizing molecules frequently found in pathogens (the so-called Pathogen-Associated Molecular Patterns—PAMPs), or molecules released by damaged cells (the Damage-Associated Molecular Patterns—DAMPs). They emerged phylogenetically prior to the appearance of the adaptive immunity and, therefore, are considered part of the innate immune system. Signals derived from the engagement of PRRs on the immune cells activate microbicidal and pro-inflammatory responses required to eliminate or, at least, to contain infectious agents. Molecularly controlled forms of cell death are also part of a very ancestral mechanism involved in key aspects of the physiology of multicellular organism, including the elimination of unwanted, damaged or infected cells. Interestingly, each form of cell death has its particular effect on inflammation and on the development of innate and adaptive immune responses. In this review article, we discuss some aspects of the molecular interplay between the cell death machinery and signals initiated by the activation of PRRs by PAMPs and DAMPs.

Phosphatidylserine (PS), a lipid normally confined to the inner leaflet of the plasma membrane, is exported to the outer plasma membrane leaflet during apoptosis to serve as a trigger for recognition of apoptotic cells by phagocytes. The mechanism of PS export during apoptosis is not known nor is it clear whether the nuclear changes that typify apoptosis contribute in any way to this event. Here, we demonstrate that ligation of the CD95 (Fas/APO-1) molecule on Jurkat cytoplasts induces dramatic PS externalization similar to that observed during apoptosis of intact cells. Apoptosis of both cells and cytoplasts was associated with proteolytic processing of CPP32, a member of the interleukin-1␤ converting enzyme (ICE)/CED-3 protease family, to its active form. Fodrin, a component of the cortical cytoskeleton, also underwent proteolytic cleavage during apoptosis of both cytoplasts and intact cells. Strikingly, CPP32 activation, fodrin proteolysis, and PS externalization were all inhibited in the presence of peptide inhibitors of ICE/CED-3 family proteases. These data provide strong support for the notion that the cell death machinery is extranuclear and is likely to be comprised of one or more members of the ICE/CED-3 family and that activation of this machinery does not require nuclear participation.Apoptosis is a mode of cell death known to be under molecular control and is central to numerous physiological and pathological processes where cells are eliminated (1-3). Although the most prominant morphological changes that occur during apoptosis typically involve the cell nucleus, studies using cytoplasts have demonstrated that the nucleus is not required for the dramatic membrane blebbing events and the subsequent loss of viability that occurs during this process (4 -6). However, it is unclear whether enucleated cells are truly apoptotic, that is, whether they can be recognized as such by macrophages and other phagocytes, as apoptotic cells are known to be (7,8). It is formally possible that although cytoplasts undergo plasma membrane blebbing and other gross features of apoptosis, they may not acquire the membrane changes that would stimulate uptake of these cells by phagocytes.Two major mechanisms appear to exist for the recognition of apoptotic cells by phagocytes; one mediated by a receptor that engages PS 1 exported to the plasma membrane during apoptosis and the other mediated by a vitronectin receptor/CD36/ thrombospondin interaction that sees an as yet unidentified ligand on the apoptotic cell (9, 10). These two mechanisms appear to be mutually exclusive because macrophages that express the PS receptor do not appear to be capable of utilizing the vitronectin receptor-associated pathway (11). Thus far, the molecular events underlying these plasma membrane changes remain unknown.Recent evidence indicates that members of the emerging ICE/CED-3 family of proteases may occupy a critical position in the cellular apparatus that effects the destructive changes within the cell during apoptosis (see Refs. 12-14 for r...

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