Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis

Area of Science:

• Immunology
• Pathology
• Molecular Biology

Background:

• Macrophage Arginase-1 (Arg1) is typically linked to promoting inflammation, fibrosis, and wound healing.
• Its precise role in Th2-mediated pathologies, such as Schistosoma mansoni infection, remains debated.

Purpose of the Study:

• To investigate the function of macrophage-specific Arginase-1 in the context of inflammation and fibrosis during Schistosoma mansoni infection.
• To elucidate the underlying mechanisms by which Arg1 influences immune responses and pathology.

Main Methods:

• Conditional deletion of the Arg1 gene in macrophages using LysMcre and Tie2cre mouse models.
• Infection with Schistosoma mansoni.
• Assessment of mortality, hepatotoxicity, endotoxemia, granulomatous inflammation, liver fibrosis, portal hypertension, and Th2 cytokine production.
• In vitro assays to evaluate macrophage-induced T cell proliferation and the role of L-arginine.

Main Results:

• Macrophage-specific deletion of Arg1 did not affect susceptibility to infection but led to accelerated mortality.
• Increased granulomatous inflammation, liver fibrosis, and portal hypertension were observed in Arg1-deficient mice.
• Arg1-deficient macrophages failed to suppress T cell proliferation in vitro, unlike wild-type alternatively activated macrophages.
• Restoration of T cell proliferation upon L-arginine supplementation indicated Arg1's role in arginine depletion.

Conclusions:

• Macrophage Arginase-1 acts as a crucial suppressor of inflammation and fibrosis, particularly in Th2-dependent responses.
• Arg1-expressing macrophages inhibit T cell proliferation by depleting L-arginine, thereby limiting exacerbated Th2 pathology.
• These findings identify Arg1 as an essential suppressive mediator of alternatively activated macrophages (AAM).