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

Abstract

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.

Macrophage regulation & function in helminth infection

“…brasiliensis infection [8,61,68], particularly at later time points following lung migration of N. brasiliensis [81]. In keeping with these studies, the activation of Chil3, Arg1 and RELMaexpressing AAMs correlated with lung repair in mice infected with Toxocara canis [82].…”

Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

“…Macrophages are phagocytes that are the first line of defence against pathogenic tissue damage. They have heterogeneous populations and are typically defined as the classically activated M1 macrophages or the alternatively activated M2 macrophages [ 124 ]. TAMs are important components of the TME and are strongly associated with poor prognosis in solid tumours, while M2-like TAMs have also been suggested to serve as prominent metastasis promoters with anti-inflammatory functions in the development of TME [ 125 , 126 ].…”

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