Nonsteroidal anti‐inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5‐lipoxygenase (LOX), or the 5‐LOX–activating protein (FLAP). These and related enzymes act in conjunction with marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to Escherichia coli , produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2). Targeted liquid chromatography–tandem mass spectrometry–based metabololipidomics was applied to analyze and quantify the specific LM profiles. Besides expected on‐target actions, we found that: 1 ) COX or 15‐LOX‐1 inhibitors elevate inflammatory leukotriene levels, 2 ) FLAP and 5‐LOX inhibitors reduce leukotrienes in M1 but less so in M2 macrophages, 3 ) zileuton blocks resolution‐initiating SPM biosynthesis, whereas FLAP inhibition increases SPM levels, and 4 ) that the 15‐LOX‐1 inhibitor 3887 suppresses SPM formation in M2 macrophages. Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation‐resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.—Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.‐E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome. FASEB J. 33, 6140–6153 (2019). www.fasebj.org

SARS-CoV-2 challenges health care systems and societies worldwide in unprecedented ways. Although numerous new studies have been conducted, research to better understand the molecular pathogen-host interactions are urgently needed.

Underlying mechanisms of how infectious inflammation is resolved by the host are incompletely understood. One hallmark of inflammation resolution is the activation of specialized pro-resolving mediators (SPMs) that enhance bacterial clearance and promote tissue repair. Here, we reveal α-hemolysin (Hla) from Staphylococcus aureus as a potent elicitor of SPM biosynthesis in human M2-like macrophages and in the mouse peritoneum through selective activation of host 15-lipoxygenase-1 (15-LOX-1). S. aureus-induced SPM formation in M2 is abolished upon Hla depletion or 15-LOX-1 knockdown. Isolated Hla elicits SPM formation in M2 that is reverted by inhibition of the Hla receptor ADAM10. Lipid mediators derived from Hla-treated M2 accelerate planarian tissue regeneration. Hla but not zymosan provokes substantial SPM formation in the mouse peritoneum, devoid of leukocyte infiltration and pro-inflammatory cytokine secretion. Besides harming the host, Hla may also exert beneficial functions by stimulating SPM production to promote the resolution of infectious inflammation.

Acute inflammation caused by bacterial infections is an essential biological defence mechanism of the host in order to neutralize and clear the invaders and to return to homeostasis. Despite its protective function, inflammation may become persistent and uncontrolled, resulting in chronic diseases and tissue destruction as consequence of the unresolved inflammatory process. Therefore, spatiotemporal induction of endogenous inflammation resolution programs that govern bacterial clearance as well as tissue repair and regeneration, are of major importance in order to enable tissues to restore functions. Lipid mediators that are de‐novo biosynthesized from polyunsaturated fatty acids (PUFAs) mainly by lipoxygenases and cyclooxygenases, critically regulate the initiation, the maintenance but also the resolution of infectious inflammation and tissue regeneration. The discovery of specialized pro‐resolving mediators (SPMs) generated from omega‐3 PUFAs stimulated intensive research in inflammation resolution, especially in infectious inflammation elicited by bacteria. SPMs are immunoresolvents that actively terminate inflammation by limiting neutrophil influx, stimulating phagocytosis, bacterial killing and clearance as well as efferocytosis of apoptotic neutrophils and cellular debris by macrophages. Moreover, SPMs prevent collateral tissue damage, promote tissue repair and regeneration and lower antibiotic requirement. Here, we review the biosynthesis of SPMs in bacterial infections and cover specific mechanisms of SPMs that govern the resolution of bacteria‐initiated inflammation.

In dermatological research, 2,4-dinitrochlorbenzene (DNCB)-induced atopic dermatitis (AD) is a standard model as it displays many disease-associated characteristics of human AD. However, the reproducibility of the model is challenging due to the lack of information regarding the methodology and the description of the phenotype and endotype of the mimicked disease. In this study, a DNCB-induced mouse model was established with a detailed procedure description and classification of the AD human-like skin type. The disease was induced with 1% DNCB in the sensitization phase and repeated applications of 0.3% and 0.5% DNCB in the challenging phase which led to a mild phenotype of AD eczema. Pathophysiological changes of the dorsal skin were measured: thickening of the epidermis and dermis, altered skin barrier proteins, increased TH1 and TH2 cytokine expression, a shift in polyunsaturated fatty acids, increased pro-resolving and inflammatory mediator formation, and dysregulated inflammation-associated gene expression. A link to type I allergy reactions was evaluated by increased mast cell infiltration into the skin accompanied by elevated IgE and histamine levels in plasma. As expected for mild AD, no systemic inflammation was observed. In conclusion, this experimental setup demonstrates many features of a mild human-like extrinsic AD in murine skin.