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Open AccessArticle

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

1
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, MEX, México
2
Servicio de Medicina Interna, Hospital General de México Dr. Eduardo Liceaga, Ciudad de México 06720, México
3
Departamento de Patología, Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Ciudad de México 14000, México
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Laboratorio de Parasitología, Facultad de Estudios Superiores Cuautitlán, UNAM, Cuautitlán I 54716, MEX, México
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Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
6
Laboratorio Nacional en Salud, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, MEX, México
*
Author to whom correspondence should be addressed.
Pathogens 2019, 8(4), 280; https://doi.org/10.3390/pathogens8040280
Received: 18 October 2019 / Revised: 22 November 2019 / Accepted: 26 November 2019 / Published: 2 December 2019
(This article belongs to the Section Immunological Responses and Immune Defense Mechanisms)
Macrophages that are classically activated (M1) through the IFN-γ/STAT1 signaling pathway have a major role in mediating inflammation during microbial and parasitic infections. In some cases, unregulated inflammation induces tissue damage. In helminth infections, alternatively activated macrophages (M2), whose activation occurs mainly via the IL-4/STAT6 pathway, have a major role in mediating protection against excessive inflammation, and has been associated with both tissue repair and parasite clearance. During the lung migratory stage of Toxocara canis, the roles of M1 and M2 macrophages in tissue repair remain unknown. To assess this, we orally infected wild-type (WT) and STAT1 and STAT6-deficient mice (STAT1−/− and STAT6−/−) with L2 T. canis, and evaluated the role of M1 or M2 macrophages in lung pathology. The absence of STAT1 favored an M2 activation pattern with Arg1, FIZZ1, and Ym1 expression, which resulted in parasite resistance and lung tissue repair. In contrast, the absence of STAT6 induced M1 activation and iNOS expression, which helped control parasitic infection but generated increased inflammation and lung pathology. Next, macrophages were depleted by intratracheally inoculating mice with clodronate-loaded liposomes. We found a significant reduction in alveolar macrophages that was associated with higher lung pathology in both WT and STAT1−/− mice; in contrast, STAT6−/− mice receiving clodronate-liposomes displayed less tissue damage, indicating critical roles of both macrophage phenotypes in lung pathology and tissue repair. Therefore, a proper balance between inflammatory and anti-inflammatory responses during T. canis infection is necessary to limit lung pathology and favor lung healing. View Full-Text
Keywords: STAT1; STAT6; M1-M2 macrophages; tissue damage-repair; parasite resistance STAT1; STAT6; M1-M2 macrophages; tissue damage-repair; parasite resistance
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    Doi: 10.5281/zenodo.3497600
    Description: Figure S1. Collagen deposition. Paraffin sections of 4µm thick from lung tissue, were Masson´s Trichrome stained and observed in microscopy light. Images were photographed with the 20x objective at 7, 28 and 60 dpi in WT, STAT1-/-, and STAT6-/- mice and collagen deposition was evaluated. Figure S2. : M1 and M2 markers after macrophages. WT, STAT1-/- and STAT6-/- mice were treated either with PBS-liposomes or clodronate-liposomes intratracheally to deplete macrophages, before and after being infected with 500 L2 T. canis larvae. The animals were euthanized at 4 dpi, lungs cells were collected, and flow cytometry was used to determine M1 or M2 activation. Representative dot plots and their respective percentage of F4/80+CD86+ (a), F4/80+IL-4Rα+ (b) and F4/80+MMR+ (c) double-positive cells are shown. Each dot plot represents an individual mouse. One-way ANOVA and Tukey's multiple comparison test. *P<0.05 comparing WT versus STAT1-/- and STAT6-/- mice. Figure S3. Numbers of cells in lung tissue. From inflammatory infiltrate in H&E stained sections the number of lymphocytes (a), macrophages (b) and PMN (c) was quantified in light microscopy (100x objective) images in WT (white bars), STAT1-/- (gray bars) and STAT6-/- (black bars) mice. Data are shown from two independent experiments as mean ± SEM (n = 6 per group) . Two-way ANOVA with Tukey multi-comparison test. *P<0.05 comparing WT versus STAT1-/- and STAT6-/-, and STAT1-/- versus STAT6-/- mice, at the same time point of infection.
MDPI and ACS Style

Faz-López, B.; Mayoral-Reyes, H.; Hernández-Pando, R.; Martínez-Labat, P.; McKay, D.M.; Medina-Andrade, I.; Olguín, J.E.; Terrazas, L.I. A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection. Pathogens 2019, 8, 280.

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