Established as a pro-inflammatory mediator, LTB4 recruitment of T cells in cancer can render the inflammatory event beneficial as CTL recruitment is a critical step for effective tumor cell killing

Established as a pro-inflammatory mediator, LTB4 recruitment of T cells in cancer can render the inflammatory event beneficial as CTL recruitment is a critical step for effective tumor cell killing. (Th1) and T helper cell type 17 (Th17) effector cells and increased the number of T regulatory cells (Tregs) in the eye draining lymph nodes [11, 12]. More importantly, sex-specific regulation of the LXA4 circuit in resident lymph nodes was identified as a key factor that drives female-specific immune-driven dry eye disease. The amplified adaptive immune response in females to routine ocular surface stress (-)-Epicatechin can be rescued by treatment with LXA4. An study showed that LXA4 promotes the differentiation of na?ve T cells into T follicular cells, which in turn induces B cells to form germinal centers [13], demonstrating that LXA4 mediates cellular signaling among lymphocytes. Direct LXA4 regulation of B cells has also been established. LXA4 treatment reduces IgG and IgM production from B cells and decreases memory B cell proliferation in an ALX/FPR2 receptor-dependent mechanism [14]; and maintain functional killing responses [17], alleviate airway inflammation by increasing NK cell-mediated eosinophil apoptosis, and reduce interleukin-13 (IL-13) release by group 2 innate lymphoid cells (ILC2) [18]. Recent reports have demonstrated that lipoxins are not only formed during inflammation and the resolution phase of inflammation, but that they are also part of normal signaling in healthy tissues and actively regulate homeostasis and the threshold for activation of immune responses in the cornea, lymph nodes, lacrimal glands and retina [11, 12, 19, 20]. Regulation and therapeutic amplification of this homeostatic SPM circuit in health and diseases is the focus of several NIH-funded projects. EPA- and DHA- derived SPM Regulation of Lymphoid-derived Cells The field of SPMs emerged from the discovery of distinct EPA- and DHA- derived mediators that shared some of the basic pro-resolving and protective actions of lipoxins and displayed potent bioactions in several inflammatory disease models. Distinct SPM receptors that were originally identified in innate leukocytes are also expressed in lymphocytes [10, 21]: FPR2/ALX for LXA4, resolvin D1 (RvD1); G protein-coupled receptor 32 (GPR32) for LXA4, RvD1; Gprotein- coupled receptor 18 (GPR18) for RvD2; chemokine-like receptor 1 (ChemR23) for resolvin E1 (RvE1) [22]. Identification of SPM receptors on Rplp1 lymphocytes [23] spurred efforts to investigate direct lymphocyte regulation by SPMs. iTreg generation [24]. This may suggest a role of SPMs in T cell lineage commitment. Several reports have also demonstrated lymphocyte regulation by RvD1 in inflammation and infection models. RvD1 treatment in LPS-induced uveitis reduces infiltration of CD4+ cells, CD8+ T cells, B cells and CD11b+ cells in the eye [25,26]. Consistent with its protective function in inflammation, RvD1 increases local Treg cell counts in the inflamed tissue in experimental autoimmune neuritis [27]. It is important to note that the DHA- derived RvD1 is a structural homolog of LXA4 and mediates its action via the same two receptors (FPR2/ALX and GPR32) as LXA4. Hence, it is expected that LXA4 and RvD1 (-)-Epicatechin have similar direct actions on lymphocytes. As a (-)-Epicatechin treatment, the RvD1 epimer 17R-RvD1 can quell infection by reducing the number of Th1 and Th17 cells and inhibiting the production of proinflammatory cytokines in stromal keratitis [28]. RvD1, like LXA4, also has direct actions on (-)-Epicatechin human B cells by suppressing IgE production and differentiation of na?ve B cells [29]. In a follow up study, RvD1 reduces IgE production by B cells in asthma patients treated with low dose steroids [30]. Other members of the SPM family such as maresin-1 (MaR1) also demonstrated its therapeutic and protective effects by restraining IL-13 cytokine production from ILCs and increasing generation of induced Tregs (iTregs) to resolve lung inflammation [31]. A receptor for MaR1 has yet to be identified, therefore it is unclear if these are direct or indirect actions on lymphocytes. Consistent with their broad protective actions in acute inflammation, SPMs downregulate effector T cell and B cell function. Hence, they are attractive therapeutic targets for controlling dysregulated innate and adaptive immune responses. A hot area of cancer research is the development of biological therapy, which is aimed at amplifying the adoptive T cell response to cancer cells. Hence, how SPM downregulation of adaptive immune responses potentially impacts immune evasion in the tumor environment needs to be investigated. LTB4 Regulation of Lymphoid-derived Cells Expression of the leukotriene B4 receptor 1 (BLT1) was identified on cells in 2003 [32, 33], and the initial findings on LTB4-mediated T cell response were investigated using allergic lung inflammation models [34]. These experiments established LTB4-mediated T cell recruitment, and implicated CD8+ T cells as the main pathogenic cell type driving allergic airway inflammation. BLT1 expression was higher on cells of.

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