Abstract
The spectrum of clinical forms observed in leprosy and its pathogenesis are dictated by the host’s immune response against Mycobacterium leprae, the etiological agent of leprosy. Previous results, based on metabolomics studies, demonstrated a strong relationship between clinical manifestations of leprosy and alterations in the metabolism of ω3 and ω6 polyunsaturated fatty acids (PUFAs), and the diverse set of lipid mediators derived from PUFAs. PUFA-derived lipid mediators provide multiple functions during acute inflammation, and some lipid mediators are able to induce both pro- and anti-inflammatory responses as determined by the cell surface receptors being expressed, as well as the cell type expressing the receptors. However, little is known about how these compounds influence cellular immune activities during chronic granulomatous infectious diseases, such as leprosy. Current evidence suggests that specialized pro-resolving lipid mediators (SPMs) are involved in the down-modulation of the innate and adaptive immune response against M. leprae and that alteration in the homeostasis of pro-inflammatory lipid mediators versus SPMs is associated with dramatic shifts in the pathogenesis of leprosy. In this review, we discuss the possible consequences and present new hypotheses for the involvement of ω3 and ω6 PUFA metabolism in the pathogenesis of leprosy. A specific emphasis is placed on developing models of lipid mediator interactions with the innate and adaptive immune responses and the influence of these interactions on the outcome of leprosy.
Highlights
Leprosy is a chronic granulomatous disease driven by interactions of the human host with Mycobacterium leprae an obligate intracellular pathogen that infects macrophages and Schwann cells of the peripheral nervous system
Through the multiple metabolomics studies performed with clinical samples from leprosy patients it is clear that alterations in the metabolism of lipid mediators derived from ω3 and ω6 polyunsaturated fatty acids (PUFAs) occur with this disease
There is a lack of research that directly links these lipid mediators to the breadth of immune responses that occur across the clinical manifestations of leprosy
Summary
Leprosy is a chronic granulomatous disease driven by interactions of the human host with Mycobacterium leprae an obligate intracellular pathogen that infects macrophages and Schwann cells of the peripheral nervous system. Lipid Mediators in Leprosy (TT) disease is typified by strong T-helper type 1 (Th1) cellular immunity and low bacterial load [2,3,4] This response promotes the protection against the pathogen via interferon-gamma (IFN-γ) activation of macrophage anti-microbicidal mechanisms [5]. The diminished Th1 response in LL is partially explained by the highly suppressive activity of T regulatory (Treg) cells and the reduced frequency of Th17 cells [4, 6] These patients manifest the most severe form of the disease and are unable to control M. leprae growth [2]. Of particular interest are the PUFA-lipid mediators: prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), leukotriene B4 (LTB4), lipoxin A4 (LXA4), and resolvin D1 (RvD1) Both PGE2 and PGD2 are found in elevated levels in the sera of LL patients as compared to BT patients [17]. We will focus the review on the five lipid mediators (PGE2, PGD2, LTB4, LXA4, and RvD1) found to be differentially produced in leprosy patients [17, 18]
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