|NELSON, SHAKIRA - Pennsylvania State University|
|SHAY, A - Pennsylvania State University|
|JAMES, JAMMAAL - Pennsylvania State University|
|CARLSON, BRADLEY - National Cancer Institute (NCI, NIH)|
|PRABHU, K - Pennsylvania State University|
Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/7/2015
Publication Date: 2/5/2016
Citation: Nelson, S.M., Shay, A.E., James, J.L., Carlson, B., Urban Jr, J.F., Prabhu, K.S. 2016. Selenoprotein expression in macrophages is critical for optimal clearance of parasitic helminth Helminth Nippostrongylus brasiliensis. Journal of Biological Chemistry. 291(6):2787-2798. doi: 10.1074/jbc.M115.684738.
Interpretive Summary: Parasitic nematode (worm) infections can produce an immune response characterized by production of certain proteins called cytokines that contribute to immunity to the infection. Diet is known to alter immune function. Selenium is a trace metal found in the diet that can modulate immune function depending on the concentration absorbed from the foods that are eaten. Here we investigated how the level of selenium in the diet could affect anti-parasite immunity leading to changes in parasite egg production and adult worm expulsion from the intestine. Mice were fed diets containing various levels of selenium and then infected with a parasitic worm called Nippostrongylus brasiliensis. Low levels of selenium in the diet inhibited immunity to the worm resulting in higher worm eggs produced and a longer time before expulsion from the intestine. Selenium-dependent immunity was linked to changes in hormones that are also affected by non-steroidal anti-inflammatory drugs (NSAIDs) commonly taken to control inflammation. This research shows that selenium in the diet can influence immunity and suggests that further studies are needed to determine if NSAIDs can also have significant effects on immunity to worm infection especially when dietary selenium is low. Other scientists and clinicians who study and treat worm infections and related metabolic disorders will benefit from these results.
Technical Abstract: The plasticity of macrophages is evident in helminthic parasite infections where they play a role in both inflammation and protection. Previously, we demonstrated that selenium (Se), in the form of selenoproteins, induced a phenotypic switch in macrophage activation from a pro-inflammatory (M1) towards an anti-inflammatory (M2) phenotype. Moreover, COX-dependent PGJ2 production is critical to this phenotypic switching. The gastrointestinal nematode parasite Nippostrongylus brasiliensis (N. brasiliensis) induces a biased Th2 response that activates M2 macrophages and contributes to parasite clearance. Here, we hypothesize that Se modulates macrophage development towards an M2 phenotype that can decrease the fecundity and increase the clearance of adult N. brasiliensis from the intestine. Se significantly augmented intestinal M2 macrophage presence, while decreasing adult worms and fecal eggs. To support the role of macrophage-specific selenoproteins in this response, we observed normal adult worm clearance and enhanced M2 marker expression in Se supplemented Trspfl/flCreWT mice that was reduced in Se supplemented Trspfl/flCreLysM mice after infection with N. brasiliensis. Studies inhibiting the COX pathway using indomethacin displayed delayed worm expulsion and enhanced egg production, as well as reduced expression of M2 markers despite high Se levels. Treatment of Se deficient mice with the PPAR-gamma endogenous agonist 15d-PGJ2, partially recapitulated the effect of Se supplementation on reduced fecal egg output by N. brasiliensis through the COX pathway. These results suggest that optimal Se status in the form of selenoproteins and Se-dependent production of anti inflammatory prostaglandins regulate M2 macrophage activation to enhance anti-helminth parasite responses.