It has been almost 90 years since the initial discovery of prostaglandins and 60 years since establishing the link between arachidonic acid (AA) and eicosanoid synthesis in which both discoveries received the Nobel Prize in Medicine. During this period, our understanding of eicosanoid functions in health and disease expanded dramatically and it is now well- established that bioactive lipids play significant roles in lung homeostatic and immune processes with a profound impact on initiation and resolution of inflammation. However, in comparison to protein-based mediators (e.g. cytokines), there is a central challenge to study host lipid mediators mainly due to their short half-life and complexity involved in detecting and measuring them. Thus, novel biological effects of bioactive lipids are still being discovered and reveal in particular the central role of macrophages orchestrating their complex functions at homeostasis and during infection.

Host defense to pulmonary infections relies on a combination of mechanisms to efficiently eliminate the invading pathogens, for example, host resistance, while preserving lung tissue integrity from damages caused by the pathogen and/or the host’ own immune response, for example, disease tolerance 1, 2, 3. During viral infections, host resistance initiates mainly via the secretion of chief antiviral cytokines, such as the type-I interferon (IFN-I), which are produced upon the recognition of the virus by toll-like receptors (e.g. TLR3, TLR7) or cytosolic receptors (e.g. RIG-I, MDA5) and activation of the transcription factor Interferon Regulatory Factor 3 (IRF3) [4]. A first wave of IFN-I, mainly interferon-β (IFN-β), is initially secreted, and signals through the IFN-α/β receptor IFNAR to induce the expression of antiviral genes and responses, including IRF7. Then, IRF7 contributes and amplifies the production of IFN-⍺ and other antiviral genes 5, 6, 7. IFN-I is produced by virtually all pulmonary cells, but we and others have shown that macrophages represent a major source of IFN-I 8•, 9, 10, 11•, 12, 13, 14. Both host resistance and disease tolerance are required for host defense against pulmonary infections, and it was further demonstrated that the crosstalk between lung macrophages, IFN-I, and eicosanoids plays a pivotal role in mediating these responses 8•, 9, 11•, 12, 15, 16, 17.

Eicosanoids are host-derived bioactive lipid mediators that are generated from AA and released upon membrane phospholipid hydrolysis by cytosolic or secreted phospholipase A2 [17]. AA is further metabolized by two main enzymatic pathways to generate a variety of eicosanoids: the cyclooxygenase pathway (COX) and the lipoxygenase pathway (LOX). A third, less-characterized, pathway (cytochrome P450) exists, which will not be discussed in this review. While the COX pathway (COX1 and COX2) results in production of prostaglandins (such as PGE2) and thromboxane, the LOX pathway (5-LOX, 12-LOX, and 15-LOX) is responsible for the generation of leukotriene B4 (LTB4), cysteinyl leukotrienes (CysLT — LTC4, LTD4, and LTE4), 12- and 15-hydroxyeicosatetraenoic acids (12-HETE and 15-HETE), and lipoxins (LXA4 and LXB4) [17]. Virtually all cells can produce eicosanoids, but macrophages constitute a major source of bioactive lipids both at steady state and during inflammation 18••, 19••. Most eicosanoids are detectable at steady state due to constitutive basal expression of the enzymes involved in their biosynthesis and play a central role in maintaining tissue development and homeostasis [17]. Nonetheless, their levels increase significantly upon infection or inflammation, triggering the expression of inducible enzymes, such as COX2 or microsomal prostaglandin-E synthase-1, and unleashing an ‘eicosanoid storm’ with both beneficial and detrimental effects on host health [17].

In this review, we will focus on the latest discoveries in the crosstalk between eicosanoids and the development and function of pulmonary macrophages.