INFLAMMASOME Stiffening up Defences

RESEARCH HIGHLIGHTS

INFLAMMASOME Stiffening up defences

against Salmonella S

b r

The activation of inflammasome to produce the antimicrobial o

signalling pathways has a central role molecules mitochondrial reactive N P

in innate immunity to Salmonella oxygen species and hydrogen G infection. However, the mechanisms peroxide. These data suggest that by which inflammasome activation the NLRC4 inflammasome restricts not Nlrc4–/– mediates intracellular bacterial intracellular bacterial numbers in BMMs exhibited a killing remain unknown. Bryant macrophages. change in their viscoelastic properties and colleagues now show that actin Using live-cell imaging, the and had increased cellular stiffness. polymerization induced by NOD-, authors observed that unlike In addition, the cellular movement LRR- and CARD-containing 4 wild-type BMMs, Nlrc4–/– BMMs of wild-type BMMs ceased rapidly (NLRC4) inflammasome activation remained readily susceptible to following infection, whereas the results in cellular stiffness and infection over time; therefore, movement of Nlrc4–/– BMMs was limits bacterial uptake and growth NLRC4 activation might alter unaffected. Reduced macrophage following infection with Salmonella cytoskeletal functions to reduce movement might help to control enterica subsp. enterica serovar bacterial uptake. Indeed, inhibition bacterial dissemination in tissues; Typhimurium. of actin polymerization in wild-type indeed, a higher number of infec- Previous studies have shown BMMs using cytochalasin D reduced tious foci was observed in the liver of that the NLRC4 and NLRP3 (NOD-, bacterial uptake and also inhibited infected Nlrc4–/– mice compared with LRR- and pyrin domain-containing 3) S. Typhimurium-induced NLRC4- wild-type mice. inflammasomes, as well as caspase 11, dependent pyroptosis. Furthermore, This study shows that NLRC4 control S. Typhimurium infection cytochalasin D inhibited the inflammasome activation by in vivo. In this study, the authors formation of ASC inflammasome Salmonella infection changes infected wild-type bone marrow- specks and NLRC4-dependent cytoskeletal dynamics, resulting in actin derived macrophages (BMMs) interleukin-1β production following increased cellular stiffness, reduced polymerization or BMMs deficient for various S. Typhimurium infection. Thus, cellular movement, decreased inflammasome components with changes in actin polymerization bacterial uptake and the production is crucial for S. Typhimurium. They found that are crucial for Salmonella-induced of antimicrobial molecules, all of Salmonella- infected BMMs lacking NLRC4 NLRC4 inflammasome activation which result in reduced intracellular induced or caspase 1, but not those lacking and reduce bacterial uptake. bacterial burden. NLRC4 NLRP3, ASC or caspase 11, had Next, the authors determined how Olive Leavy a significantly higher bacterial S. Typhimurium-induced NLRC4 ORIGINAL RESEARCH PAPER Man, S. M. et al. inflammasome burden than wild-type cells. Unlike activation results in changes in Actin polymerization as a key innate immune activation wild-type and Nlrp3–/– BMMs, cytoskeletal functions. They found effector mechanism to control Salmonella infection. Proc. Natl Acad. Sci. USA 11, 17588–17593 (2014) Nlrc4–/– and Casp1–/– BMMs failed that infected wild-type BMMs but

NATURE REVIEWS | IMMUNOLOGY VOLUME 15 | JANUARY 2015