title: Vitamin D Promotes Pneumococcal Killing and Modulates Inflammatory Responses in Primary Human Neutrophils.
abstract: Streptococcus pneumoniae is a major human pathogen and a leading cause of pneumonia, septicemia, and meningitis worldwide. Despite clinical studies linking vitamin D deficiency and pneumonia, molecular mechanisms behind these observations remain unclear. In particular, the effects of vitamin D on neutrophil responses remain unknown. Using pneumococcal strains, primary neutrophils isolated from human blood, and sera from patients with frequent respiratory tract infections (RTIs), we investigated the effects of vitamin D on neutrophil bactericidal and inflammatory responses, including pattern recognition receptors, antimicrobial peptides, and cytokine regulation. We found that vitamin D upregulated pattern recognition receptors, TLR2, and NOD2, and induced the antimicrobial human neutrophil peptides (HNP1-3) and LL-37, resulting in increased killing of pneumococci in a vitamin D receptor-dependent manner. Antibodies targeting HNP1-3 inhibited bacterial killing. Vitamin D supplementation of serum from patients with bacterial RTIs enhanced neutrophil killing. Moreover, vitamin D lowered inflammatory cytokine production by infected neutrophils via IL-4 production and the induction of suppressor of cytokine signaling (SOCS) proteins SOCS-1 and SOCS-3, leading to the suppression of NF-κB signaling. Thus, vitamin D enhances neutrophil killing of S. pneumoniae while dampening excessive inflammatory responses and apoptosis, suggesting that vitamin D could be used alongside antibiotics when treating pneumococcal infections.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karthik
authors.initials: K
authors.lastname: Subramanian
authors.forename: Peter
authors.initials: P
authors.lastname: Bergman
authors.forename: Birgitta
authors.initials: B
authors.lastname: Henriques-Normark
mesh_terms: D001433:Bacteriolysis; D002478:Cells, Cultured; D006801:Humans; D056747:Immunomodulation; D007249:Inflammation / Q000188:drug therapy*; D015847:Interleukin-4 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D011008:Pneumococcal Infections / Q000188:drug therapy*; D061251:Primary Cell Culture; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D014807:Vitamin D / Q000494:pharmacology*; D023084:alpha-Defensins / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C108944:SOCS1 protein, human; C106643:SOCS2 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D023084:alpha-Defensins; D014807:Vitamin D; D015847:Interleukin-4
keywords: Alpha-defensins; Human neutrophil peptides; Immunomodulation; Interleukin-4; Neutrophils; Pneumococci; SOCS-1; SOCS-3; Streptococcus pneumoniae; Suppressor of cytokine signaling; Vitamin D