Selenoprotein Expression in Macrophages Is Critical for Optimal Clearance of Parasitic Helminth Nippostrongylus brasiliensis

Abstract

The plasticity of macrophages is evident in helminthic parasite infections, providing protection from inflammation. Previously we demonstrated that the micronutrient selenium induces a phenotypic switch in macrophage activation from a classically activated (pro-inflammatory; M1/CAM) toward an alternatively activated (anti-inflammatory; M2/AAM) phenotype, where cyclooxygenase (COX)-dependent cyclopentenone prostaglandin J 2 (15d-PGJ 2 ) plays a key role. Here, we hypothesize that dietary selenium modulates macrophage polarization toward an AAM phenotype to assist in the increasing clearance of adult Nippostrongylus brasiliensis, a gastrointestinal nematode parasite. Mice on a selenium-adequate (0.08 ppm) diet significantly augmented intestinal AAM presence while decreasing adult worms and fecal egg production when compared with infection of mice on selenium-deficient (<0.01 ppm) diet.

IL-4 up-regulates cyclooxygenase-1 expression in macrophages

“…Finally, IL-4 stimulation led to approximately a 10-fold increase in the expression of M2 macrophages that was previously shown to be sensitive to indomethacin (Fig. 1E) (17). Macrophages were first gated by their forward and side scatter characteristics followed by CD11b ϩ F480 ϩ cells, which consisted of ϳ98% of the macrophage population, and were further gated on CD206 ϩ and Arg-1 ϩ (supplemental Fig.…”

“…To extend the analysis of mTORC signaling and Cox-1 in macrophages, we showed that the production of 15d-PGJ 2 was significantly increased with IL-4 stimulation, which was inhibited upon loss of Cox-1 expression by torin 1 as well as metformin. Our data suggested that Cox-1 functionally couples with H-PGDS to likely provide the ligand (15d-PGJ 2 ) to PPAR␥, which acts in concert with Stat6 to activate transcription of PPAR␥ target genes to aid in macrophage (M2) polarization (15)(16)(17)45). More importantly, inhibition of mTORC by metformin, which negatively impacted M2 macrophage polarization through decrease in Cox-1 expression, was rescued by exogenous treatment with 15d-PGJ 2 suggesting the importance of Cox-1 activity in macrophage function.…”

“…Treatment with metformin has been shown to significantly reduce the IL-13-induced expression of M2 macrophage markers, such as CD206 (14). However, little is known about how metformin treatment affects the production of endogenous ligands, ⌬ 12 -prostaglandin (PG) J 2 and 15-deoxy-⌬-12,14 -PGJ 2 (15d-PGJ 2 ) that are known to activate PPAR-␥ and affect polarization of macrophages (15)(16)(17)(18). This is particularly interesting because IL-4/ IL-13 significantly down-regulate the expression of Cox-2 (19,20).…”

“…More importantly, Cox-1 functionally couples with H-PGDS to form PGD 2 and its downstream products (25,26). Treatment with indomethacin, a nonselective Cox inhibitor, led to decreased M2 macrophage markers in vivo as well as increased N. brasiliensis burden, which was reversed by exogenous treatment with 15d-PGJ 2 (17).…”

“…6). This is relevant because Cox activity is required to generate bioactive prostanoids, particularly PGJ 2 metabolites, that serve as endogenous ligands for PPAR␥ and drive macrophage polarization (15)(16)(17)48). As shown here, only Cox-1, and not Cox-2, was expressed both in vitro and in vivo during a Th2-mediated response emphasizing the need to better understand the role of Cox-1 to enable development of new and more specific therapeutic regimens in addition to understanding how current drugs, such as metformin, may have unintentional effects on Cox regulation.…”