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Title: Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion

Author
item CHEN, FEI - New Jersey Medical School
item WU, WENHUI - New Jersey Medical School
item MILLMAN, AREIEL - New Jersey Medical School
item CRAFT, J - University Of California
item CHEN, E - University Of California
item PATEL, N - New Jersey Medical School
item BOUCHER, J - University Of California
item Urban, Joseph
item KIM, C - University Of California
item GAUSE, W - New Jersey Medical School

Submitted to: Nature Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/31/2014
Publication Date: 10/15/2014
Citation: Chen, F., Wu, W., Millman, A., Craft, J.F., Chen, E., Patel, N., Boucher, J.L., Urban Jr, J.F., Kim, C.C., Gause, W.C. 2014. Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion. Nature Immunology. 15(10):938-946. doi: 10.1038/ni.2984.

Interpretive Summary: Parasitic nematode (worm) infections can produce an immune response and allergic inflammation similar to responses to food and airborne allergens. Migration of larval stages of certain parasites through the lungs can establish conditions for more reactive responses following a re-exposure to the parasite or an allergen. Understanding this mechanism and the cells that contribute to the response would be helpful in the control of parasite infection in humans and livestock as well as for the control of allergic disease in general. This study showed that combinations of different cell populations that respond to the migration of the parasite in the lungs activate changes that facilitate destruction of the parasite during a second infection. These cells localize in the lung tissue and persist for long periods after the initial infection. The positive benefit of this observation is that these cells can be targeted for vaccine studies to protect against infection, but they can also react against common allergens to induce lung inflammation that could be detrimental. Strategies to reduce the reactivity of these cells, including the use of dietary treatments, can now be developed to limit the negative effects of these long lived cell populations in the lung. Other scientists and clinicians who study and treat worm infections and related allergic disorders will benefit from these results.

Technical Abstract: The innate immune cell populations that mediate metazoan parasite expulsion remain largely undefined. We examined the role of innate cells in the immune response to the nematode parasite Nippostrongylus brasiliensis hypothesizing that they may mediate the markedly accelerated CD4+ T cell-independent worm clearance following a secondary inoculation. Immunofluorescence microscopy demonstrated a localized infiltrate of macrophages and eosinophils surrounding parasitic larvae in the lung after secondary inoculation, and lung larvae showed reduced ATP, indicating impaired metabolism. Transfer of macrophages from N. brasiliensis-primed wild-type (WT) mice as late as one month after inoculation accelerated parasite clearance after primary inoculation. Macrophages from primed WT, but not Il4ra-/- mice, adhered to third-stage larvae (L3) in vitro and triggered decreased L3 metabolism and increased L3 mortality. Neutrophil (Ly6G+) depletion blocked protective immunity after secondary inoculation and depletion of neutrophils in primed mice blocked the protective effects of transferred macrophages in recipient mice and inhibited cell binding to L3 in vitro. These data indicate that neutrophils in the context of a type 2 cytokine environment prime a long-lived effector macrophage phenotype that can subsequently bind metazoan parasites and directly mediate rapid worm damage and clearance.