The role of leukotriene B4 in early stages of experimental paracoccidioidomycosis induced in phenotypically selected mouse strains

Abstract

Paracoccidioidomycosis is a human systemic mycosis caused by the fungus Paracoccidioides brasiliensis. The mechanisms involved in innate immune response to this fungus are not fully elucidated. Leukotrienes are known to be critical for the clearance of various microorganisms, mainly by mediating the microbicidal function of phagocytes. We investigated the involvement of leukotriene B4 in the early stages of experimental paracoccidioidomycosis, which was induced by intratracheal inoculation of the fungus in selected mouse lines. The mouse lines utilized were produced through bi-directional phenotypic selection, endowed with maximal or minimal acute inflammatory reactivity, and designated AIRmax and AIRmin, respectively. AIRmax mice were more resistant to the infection, which was demonstrated by reduced lung fungal loads. However, the two lines produced similar amounts of leukotriene B4, and pharmacological inhibition of this mediator provoked similar fungal load increases in the two lines. The lower fungal load in the AIRmax mice was associated with a more effective inflammatory response, which was characterized by enhanced recruitment and activation of phagocytic cells and an increased production of activator cytokines. This process resulted in an increased release of fungicidal molecules and a diminution of fungal load. In both lines, leukotriene production was associated with a protective response in the lung that was consequent to the effect of this eicosanoid on the influx and activation of phagocytes.

Host-Derived Leukotriene B4 Is Critical for Resistance against Invasive Pulmonary Aspergillosis

“…Moreover, exogenous LTB 4 and LTD 4 can enhance phagocytosis and killing of C. albicans by macrophages ( 19 ). Finally, LTB 4 -mediated inflammation is critical for host resistance and neutrophil recruitment during Histoplasma capsulatum ( 20 , 21 ), and Paracoccidioides brasiliensis ( 22 , 23 ) infection. Moreover, LTB 4 -mediated inflammation is critical for establishing memory T cells for the prevention of histoplasmosis ( 24 ).…”

Lipoxin Inhibits Fungal Uptake by Macrophages and Reduces the Severity of Acute Pulmonary Infection Caused by Paracoccidioides brasiliensis

“…The role played by LTs in murine paracoccidioidomycosis is still controversial. Pharmacological inhibition of LT synthesis employing the FLAP inhibitor MK 886 [ 35 ] showed a protective effect of LTB 4 in the early pulmonary infection developed by two mouse strains selected for high and low inflammatory responses [ 35 ]. However, two recent reports using 5-LO deficient C57BL/6 mice reported opposite results.…”

Cytotoxic Activity and Lymphocyte Subtypes in Mice Selected for Maximal and Minimal Inflammatory Response after Transplantation of B16F10 and S91 Melanoma Cells

“…Furthermore, AIRmax neutrophils were more resistant to apoptosis [ 13 ]. AIRmax is more resistant to infection by Salmonella enterica serotype Typhimurium [ 4 ], Trypanosoma cruzi [ 14 ], and Paracoccidioides brasiliensis [ 15 ]. Contrarily, AIRmax is susceptible to pristane-induced arthritis [ 5 ], experimental autoimmune uveitis [ 16 ], and IgA glomerulonephritis experimental model [ 17 ].…”