Macrophage Activation Redirects Yersinia-Infected Host Cell Death from Apoptosis to Caspase-1-Dependent Pyroptosis

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Abstract
Infection of macrophages by Yersinia species results in YopJ-dependent apoptosis, and naïve macrophages are highly susceptible to this form of cell death. Previous studies have demonstrated that macrophages activated with lipopolysaccharide (LPS) prior to infection are resistant to YopJ-dependent cell death; we found this simultaneously renders macrophages susceptible to killing by YopJ− Yersinia pseudotuberculosis (Yptb). YopJ− Yptb-induced macrophage death was dependent on caspase-1 activation, resulting in rapid permeability to small molecules, followed by membrane breakdown and DNA damage, and accompanied by cleavage and release of proinflammatory interleukin-18. Induction of caspase-1-dependent death, or pyroptosis, required the bacterial type III translocon but none of its known translocated proteins. Wild-type Yptb infection also triggered pyroptosis: YopJ-dependent activation of proapoptotic caspase-3 was significantly delayed in activated macrophages and resulted in caspase-1-dependent pyroptosis. The transition to susceptibility was not limited to LPS activation; it was also seen in macrophages activated with other Toll-like receptor (TLR) ligands and intact nonviable bacteria. Yptb infection triggered macrophage activation and activation of caspase-1 in vivo. Y. pestis infection of activated macrophages also stimulated caspase-1 activation. These results indicate that host signaling triggered by TLR and other activating ligands during the course of Yersinia infection redirects both the mechanism of host cell death and the downstream consequences of death by shifting from noninflammatory apoptosis to inflammatory pyroptosis. Pathogenic Yersinia are bacteria capable of interacting with host immune cells and inhibiting their function. Macrophages are potent antimicrobial immune cells that eliminate invading microbes, and represent a major target for Yersinia during infection. Yersinia triggers death of resting macrophages by apoptosis, a process thought to be advantageous for Yersinia growth during early stages of infection because important host cells are eliminated without perturbing the surrounding tissue. However, activated macrophages with enhanced antimicrobial activity play a crucial role in controlling Yersinia infection. To elucidate the mechanisms involved in successful defense against infection, the authors investigated the response of activated macrophages to Yersinia, which revealed induction of a proinflammatory cell death pathway termed pyroptosis. Unlike apoptosis, pyroptosis unleashes inflammatory mediators capable of enhancing immune responses and clearing bacteria. Macrophage activation and pyroptosis was observed in infected host tissue. Thus, regulating the mechanism of cell death is important for effective responses to Yersinia infection: activated macrophages resisting apoptosis are redirected to utilize pyroptosis, an inflammatory process facilitating host resistance.