Hematopoietic cell-derived RELMα regulates hookworm immunity through effects on macrophages

Area of Science:

• Immunology
• Parasitology
• Molecular Biology

Background:

• Resistin-like molecule alpha (RELMα) is a secreted protein involved in type 2 (Th2) inflammatory responses, such as helminth infection and allergy.
• RELMα is produced by both immune cells and epithelial cells (EC), but the distinct functional roles of immune- versus EC-derived RELMα remain unclear.

Purpose of the Study:

• To investigate the functional impact of immune cell-derived RELMα in helminth infection.
• To elucidate the mechanisms by which RELMα modulates immune responses and parasite clearance.

Main Methods:

• Generation of bone marrow (BM) chimeras with RELMα deficiency in either BM or non-BM cells.
• Infection of mice with Nippostrongylus brasiliensis (Nb) and assessment of inflammatory responses, parasite burden, and Th2 cytokine levels.
• Macrophage-worm co-culture system to analyze RELMα's effect on macrophage-mediated parasite killing.
• Gene expression analysis of macrophages to identify signaling pathways regulated by RELMα.

Main Results:

• Mice lacking RELMα in bone marrow cells (BM RELMα-/-) exhibited increased lung and intestinal inflammation and enhanced parasite killing during Nb infection.
• CD11c+ lung macrophages were identified as a major source of BM-derived RELMα and mediate parasite killing.
• RELMα-deficient macrophages showed increased binding to Nb and impaired parasite development, which was partially reversed by recombinant RELMα.
• RELMα was found to decrease cell adhesion and Fc receptor signaling pathways in macrophages.

Conclusions:

• Bone marrow-derived RELMα is essential for dampening immune responses against Nb infection.
• RELMα functions as an immune brake by inhibiting macrophage recruitment and interaction with the parasite, thereby limiting tissue damage.
• These findings suggest a mutually beneficial role for RELMα in host-parasite interactions by controlling inflammation and parasite expulsion.