Role of Macrophages in the Repair Process during the Tissue Migrating and Resident Helminth Infections

The Th1/Th2/Th17 balance is a fundamental feature in the regulation of the inflammatory microenvironment during helminth infections, and an imbalance in this paradigm greatly contributes to inflammatory disorders. In some cases of helminthiasis, an initial Th1 response could occur during the early phases of infection (acute), followed by a Th2 response that prevails in chronic infections. During the late phase of infection, alternatively activated macrophages (AAMs) are important to counteract the inflammation caused by the Th1/Th17 response and larval migration, limiting damage and repairing the tissue affected. Macrophages are the archetype of phagocytic cells, with the primary role of pathogen destruction and antigen presentation. Nevertheless, other subtypes of macrophages have been described with important roles in tissue repair and immune regulation. These types of macrophages challenge the classical view of macrophages activated by an inflammatory response. The role of these subtypes of macrophages during helminthiasis is a controversial topic in immunoparasitology. Here, we analyze some of the studies regarding the role of AAMs in tissue repair during the tissue migration of helminths

Signal Transducer and Activator of Transcription Factor 6 Signaling Contributes to Control Host Lung Pathology but Favors Susceptibility against Toxocara canis Infection

Using STAT6−/− BALB/c mice, we have analyzed the role of STAT6-induced Th2 response in determining the outcome of experimental toxocariasis caused by embryonated eggs of the helminth parasite Toxocara canis. Following T. canis infection wild-type BALB/c mice developed a strong Th2-like response, produced high levels of IgG1, IgE, and IL-4, recruited alternatively activated macrophages, and displayed a moderate pathology in the lungs; however, they harbored heavy parasite loads in different tissues. In contrast, similarly infected STAT6−/− BALB/c mice mounted a weak Th2-like response, did not recruit alternatively activated macrophages, displayed a severe pathology in the lungs, but efficiently controlled T. canis infection. These findings demonstrate that Th2-like response induced via STAT6-mediated signaling pathway mediates susceptibility to larval stage of T. canis. Furthermore, they also indicate that unlike most gastrointestinal helminths, immunity against larvae of T. canis is not mediated by a Th2-dominant response

TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells

Abstract Background Human endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are, respectively, encoded by adjacent X-linked genes. We previously established that TLR7 evades X chromosome inactivation (XCI) in female immune cells. Whether TLR8 also evades XCI, however, has not yet been explored. Method In the current study, we used RNA fluorescence in situ hybridization (RNA FISH) to directly visualize, on a single-cell basis, primary transcripts of TLR7 and TLR8 relative to X chromosome territories in CD14+ monocytes and CD4+ T lymphocytes from women, Klinefelter syndrome (KS) men, and euploid men. To assign X chromosome territories in cells lacking robust expression of a XIST compartment, we designed probes specific for X-linked genes that do not escape XCI and therefore robustly label the active X chromosome. We also assessed whether XCI escape of TLR8 was associated with sexual dimorphism in TLR8 protein expression by western blot and flow cytometry. Results Using RNA FISH, we show that TLR8, like TLR7, evades XCI in immune cells, and that cells harboring simultaneously TLR7 and TLR8 transcript foci are more frequent in women and KS men than in euploid men, resulting in a sevenfold difference in frequency. This transcriptional bias was again observable when comparing the single X of XY males with the active X of cells from females or KS males. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in male cells. Conclusions TLR8, mirroring TLR7, escapes XCI in human monocytes and CD4+ T cells. Co-dependent transcription from the active X chromosome and escape from XCI could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases

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

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