Leukotriene B4 licenses inflammasome activation to enhance skin host defense.

The initial production of inflammatory mediators dictates host defense as well as tissue injury. Inflammasome activation is a constituent of the inflammatory response by recognizing pathogen and host-derived products and eliciting the production of IL-1ß and IL-18 in addition to inducing a type of inflammatory cell death termed "pyroptosis." Leukotriene B4 (LTB4) is a lipid mediator produced quickly (seconds to minutes) by phagocytes and induces chemotaxis, increases cytokine/chemokine production, and enhances antimicrobial effector functions. Whether LTB4 directly activates the inflammasome remains to be determined. Our data show that endogenously produced LTB4 is required for the expression of pro-IL-1ß and enhances inflammasome assembly in vivo and in vitro. Furthermore, LTB4-mediated Bruton's tyrosine kinase (BTK) activation is required for inflammasome assembly in vivo as well for IL-1ß-enhanced skin host defense. Together, these data unveil a new role for LTB4 in enhancing the expression and assembly of inflammasome components and suggest that while blocking LTB4 actions could be a promising therapeutic strategy to prevent inflammasome-mediated diseases, exogenous LTB4 can be used as an adjuvant to boost inflammasome-dependent host defense.

Intestinal host defense outcome is dictated by PGE2 production during efferocytosis of infected cells.

Inflammatory responses are terminated by the clearance of dead cells, a process termed efferocytosis. A consequence of efferocytosis is the synthesis of the antiinflammatory mediators TGF-ß, PGE2, and IL-10; however, the efferocytosis of infected cells favors Th17 responses by eliciting the synthesis of TGF-ß, IL-6, and IL-23. Recently, we showed that the efferocytosis of apoptotic Escherichia coli-infected macrophages by dendritic cells triggers PGE2 production in addition to pro-Th17 cytokine expression. We therefore examined the role of PGE2 during Th17 differentiation and intestinal pathology. The efferocytosis of apoptotic E. coli-infected cells by dendritic cells promoted high levels of PGE2, which impaired IL-1R expression via the EP4-PKA pathway in T cells and consequently inhibited Th17 differentiation. The outcome of murine intestinal Citrobacter rodentium infection was dependent on the EP4 receptor. Infected mice treated with EP4 antagonist showed enhanced intestinal defense against C. rodentium compared with infected mice treated with vehicle control. Those results suggest that EP4 signaling during infectious colitis could be targeted as a way to enhance Th17 immunity and host defense.

RIP2 Contributes to Expanded CD4+ T Cell IFN-γ Production during Efferocytosis of Streptococcus pneumoniae-Infected Apoptotic Cells.

Apoptotic cell clearance by professional and nonprofessional phagocytes in the process of efferocytosis is critical to preserve tissue homeostasis. Uptake of apoptotic cells by dendritic cells generates regulatory T cells and induces immunologic tolerance against self-antigens. In contrast, ingestion of infected apoptotic cells promotes activation of TLR4/MyD88-dependent bone marrow-derived dendritic cells (BMDCs) and triggers Th17 cell differentiation. In this study, we evaluated the impact of Streptococcus pneumoniae-infected apoptotic cell efferocytosis by BMDCs derived from C57BL/6 mice on differentiation and expansion of CD4+ T cell subsets, as well as the role of TLR2/4 and receptor-interacting protein 2 (RIP2) receptors in recognizing intracellular pathogens during efferocytosis. We demonstrated that BMDC-mediated efferocytosis of S. pneumoniae-infected apoptotic cells induced Th1 cell differentiation and expansion. Although TLR2/4 and RIP2 deficiency in BMDCs did not affect Th1 cell differentiation during efferocytosis, the absence of RIP2 decreased IFN-γ production by CD4 T cells during the expansion phase. These findings suggest that RIP2-mediated IL-1ß production during efferocytosis of S. pneumoniae-infected apoptotic cells partially supports a Th1-mediated IFN-γ production microenvironment.