An oily, sustained counter-regulatory response to TB

Abstract

Lipoxins are potent antiinflammatory lipid mediators that restrain and promote the resolution of a wide variety of inflammatory processes. Recent studies implicating deficient lipoxin production in the pathogenesis of diverse inflammatory diseases, along with numerous reports of the beneficial effects of lipoxin analog administration in animal models of inflammatory pathology, have suggested that harnessing the pleiotropic activities of the lipoxins is a strategy with considerable therapeutic promise. In this issue of the JCI, Bafica et al. address the other side of the coin, reporting that endogenous lipoxins compromise immune-mediated control of Mycobacterium tuberculosis infection in mice. In addition to providing novel insight into the mechanisms that interfere with the development of protective immune responses to M. tuberculosis, the study raises the possibility that pharmacological inhibition of lipoxin synthesis may provide a method of augmenting inefficient immune responses in TB and other important chronic infectious diseases.

Figure 1

Lipoxin biosynthesis. There are at least 3 different biosynthetic pathways for lipoxin generation. All lead to the insertion of molecular oxygen at 2 sites in arachidonic acid by a variety of different enzymes that are generally segregated in different cell types and subject to regulation by cytokines and other inflammatory stimuli. In the first pathway (A), LXA₄ is generated through the action of 15-LO from airway epithelia or myeloid cells (neutrophils, monocyte/macrophages), which is followed by the action of 5-LO in myeloid cells. In the second pathway (B), LXA₄ is generated from leukotriene A₄ (LTA₄) (itself a product of 5-LO activity, and a leukotriene precursor) through the action of 15-LO or platelet-derived 12-LO. In the third pathway (C), arachidonic acid is converted to aspirin-triggered lipoxins (ATLs) such as 15-epi-LXA₄, via the action of epithelial or endothelial COX-2 in the presence of aspirin, which is followed by the action of 5-LO. The ATLs have similar activities but greater functional potency due to their relative resistance to metabolic inactivation. These pathways likely operate both independently and in a coregulated fashion in different tissues and biological situations. H(p)ETE, hydroperoxyeicosatetraenoic acid; mono, monocyte/macrophage; PMN, polymorphonuclear neutrophil.