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The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a multimeric protein complex that mediates maturation of the cytokines IL-1β and IL-18 as well as release of the proinflammatory protein high-mobility group box 1 (HMGB1) and contributes to several inflammatory diseases, including sepsis, gout, and type 2 diabetes. In this context, the well-studied active complement fragment C5a and its receptor C5aR1 or C5aR2 orchestrate the inflammatory responses in many diseases. Although a C5a-C5aR interaction in NLRP3-associated diseases has been suggested, little is known about the details of C5a-C5aR cross-talk with the NLRP3 inflammasome in macrophages. In this study, using mice and murine macrophages and cytokines, immunoblotting, siRNA, and quantitative real-time PCR assays, we demonstrate that C5aR2 deficiency restricts activation of the NLRP3 inflammasome and release of HMGB1 both in vitro and in vivo. Mechanistically, we found that C5aR2 promotes NLRP3 activation by amplifying dsRNA-dependent PKR expression, which is an important NLRP3-activating factor. We also observed that elevation of PKR expression because of the C5a-C5aR2 interaction depends on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase pathway and type I IFN signaling. In conclusion, these findings reveal that C5aR2 contributes to NLRP3 inflammasome activation and HMGB1 release from macrophages. [ABSTRACT FROM AUTHOR]

We previously reported that Plasmodium infection promotes antitumor immunity in a murine Lewis lung cancer. In this study, we investigated the effects of Plasmodium infection on the tumor inhibition and antitumor CD8+ T cell responses in a murine triple negative breast cancer (TNBCA) model. The results showed that Plasmodium infection significantly inhibited tumor growth, and increased the survival rate of the tumor-bearing mice. Both effector and memory CD8+ T cells were increased in peripheral blood and tumor-draining lymph node (DLN) in the infected mice. The co-stimulatory (CD40L, GITR and OX-40) and co-inhibitory (PD-1, CTLA-4, TIM-3, LAG3) immune checkpoints were up-regulated on CD8+ T cells in infected mice. Importantly, Py induced remarkable effects on the infiltration of CD8+ T cells in the tumor and granzym B+ CD8+ T cells in tumor-bearing mice while not in tumor-free mice. In summary, the results suggested that the effects of Plasmodium infection on murine 4T1 breast cancer might be related to the induction of CD8+ T cell-mediated antitumor immune responses. This finding may provide a novel strategy for the treatment of triple negative breast cancer. Graphic summary for Plasmodium infection inhibiting triple negative 4T1 breast cancer potentially through induction of CD8+ T cell-mediated antitumor responses in mice [Display omitted] • Plasmodium infection inhibited tumor growth and increased the survival rate of triple negative 4T1 breast cancer-bearing mice. • Plasmodium infection increased the proportion of CD8+ effector and memory T cells in the infected mice. • Plasmodium infection induced remarkable effects on granzym B+ CD8+ T cell in tumor-bearing mice while not in tumor-free mice. • Plasmodium infection promoted the infiltration of CD8+ T cells in the tumor tissues of the triple negative 4T1 breast cancer-bearing mice. [ABSTRACT FROM AUTHOR]