Eicosanoid and Specialized Proresolving Mediator Regulation of Lymphoid Cells

Abstract

Eicosanoids and specialized proresolving mediators (SPMs) regulate leukocyte function and inflammation. They are ideally positioned at the interface of the innate and adaptive immune responses when lymphocytes interact with leukocytes. Receptors for leukotriene B₄ (LTB₄), prostaglandin E₂ (PGE₂), and SPMs are expressed on lymphocytes. Evidence points toward an essential role of these lipid mediators (LMs) in direct regulation of lymphocyte functions. SPMs, which include lipoxins, demonstrate comprehensive protective actions with lymphocytes. LTB₄ and PGE₂ regulation of lymphocytes is diverse and depends on the interaction of lymphocytes with other cells. Importantly, both LTB₄ and PGE₂ are essential regulators of T cell antitumor activity. These LMs are attractive therapeutic targets to control dysregulated innate and adaptive immune responses, promote lymphocyte antitumor activity, and prevent tumor immune evasion.

Figure 1.

Direct immune regulation of lymphoid cells by SPMs and eicosanoids during inflammation. Lipid mediators and inflammation are conceptually and functionally closely intertwined. Upon cellular activation, lipid mediators are synthesized de novo locally and rapidly metabolized at the site of inflammation to modulate the immune response. SPMs and eicosanoids can directly inhibit or promote lymphocytes functions as depicted by symbols representing migration, proliferation, antibody production, cytotoxicity, activation, differentiation, development and cytokine production. Eicosanoids and SPMs mediate intracellular communication in a cell -specific approach.

Figure 2.

Direct immune regulation of lymphoid cells by SPMs and eicosanoids in cancer. Tumor COX-2 expression induces PGE₂ production and tumor growth in a self-feedback loop manner. PGE₂ increases angiogenesis that facilitates tumor growth and metastasis, as well as promote the differentiation of Treg to help tumors evade immune surveillance. Actions of COX-2 and PGE2 are inhibited by NSAIDs. Lipoxins and SPMs have broad actions that result in inhibition metastasis, angiogenesis and/or inflammatory cytokine production. LTB₄ can have dichotomous functions on lymphocytes in the tumor environment promoting tumor metastasis via upregulating the expression of PPAR□ in Bregs, and on the other hand directly recruiting CTLs to tumors to enhance tumor killing.

Figure 3.

Eicosanoid and SPM biosynthetic pathways in lymphocytes and lymph nodes. a) Eicosanoids and SPMs formed in mouse and human lymph nodes. Indicated are the number of structurally distinct and bioactive resolvins, protectins and resolvin/protectin/maresin glutathione conjugates (PCTR, MCTR, RCTR) that have been documented in human lymph nodes [85, 86]. Gray-colored cells indicating unidentified cellular source of eicosanoids. PMN= neutrophil; 5-LOX= 5-lipoxygenase; FLAP= 5-lipoxygenase activating protein; 12/15-LOX= 12/15-lipoxygenase; COX= cyclooxygenase. b) Direct LTB₄ formation by virus infected CD4+ T cells, and direct PGE₂ formation by CD4+ T cells upon T cell receptor stimulation. c) Transcellular generation of a protectin glutathione-conjugate, protectin conjugates in tissue regeneration (PCTR) by innate lymphoid cell type 3 (ILC3). ILC3 in presence of DHA forms 17-HDHA, which then is converted by macrophages (MØ) to CTR.