RELMα-expressing macrophages protect against fatal lung damage and reduce parasite burden during helminth infection

In the RELMα realm Alternatively activated macrophages (AAMs) are critical to many different immune responses. Krljanac et al. developed a tool to track and characterize AAMs based on expression of the immunomodulatory protein resistin-like molecule (RELM) α. They generated RELMα reporter/deleter mice and observed that RELMα+ macrophages are enriched in white adipose tissue, gut, and peritoneum at steady state. Primary infection with the helminth Nippostrongylus brasiliensis induces expansion of RELMα+ lung interstitial macrophages but not alveolar macrophages in a STAT6-dependent manner. The presence of RELMα+ macrophages was required for protection from fatal primary infection and resistance against secondary infection. Together, these data define RELMα as a marker of AAMs and reveal its role in defense against helminth infection in the lung. Alternatively activated macrophages (AAMs) can contribute to wound healing, regulation of glucose and fat metabolism, resolution of inflammation, and protective immunity against helminths. Their differentiation, tissue distribution, and effector functions are incompletely understood. Murine AAMs express high levels of resistin-like molecule (RELM) α, an effector protein with potent immunomodulatory functions. To visualize RELMα+ macrophages (MΦs) in vivo and evaluate their role in defense against helminths, we generated RELMα reporter/deleter mice. Infection with the helminth Nippostrongylus brasiliensis induced expansion of RELMα+ lung interstitial but not alveolar MΦs in a STAT6-dependent manner. RELMα+ MΦs were required for prevention of fatal lung damage during primary infection. Furthermore, protective immunity was lost upon specific deletion of RELMα+ MΦs during secondary infection. Thus, RELMα reporter/deleter mice reveal compartmentalization of AAMs in different tissues and demonstrate their critical role in resolution of severe lung inflammation and protection against migrating helminths. RetnlaCre fate mapping mice reveal differentiation, tissue localization, and in vivo functions of RELMα+ macrophages. RetnlaCre fate mapping mice reveal differentiation, tissue localization, and in vivo functions of RELMα+ macrophages.