Plasmacytoid dendritic cells (pDC) are a specialized sensor of viral and bacterial nucleic acids and a major producer of IFN-α that promotes host defense by priming both innate and acquired immune responses. Although synthetic Toll-like receptor (TLR) ligands, pathogenic bacteria and viruses activate pDC, there is limited investigation of non-pathogenic microbiota that are in wide industrial dietary use, such as lactic acid bacteria (LAB). In this study, we screened for LAB strains, which induce pDC activation and IFN-α production using murine bone marrow (BM)-derived Flt-3L induced dendritic cell culture. Microbial strains with such activity on pDC were absent in a diversity of bacillary strains, but were observed in certain spherical species ( Lactococcus , Leuconostoc, Streptococcus and Pediococcus ), which was correlated with their capacity for uptake by pDC. Detailed study of Lactococcus lactis subsp. lactis JCM5805 and JCM20101 revealed that the major type I and type III interferons were induced (IFN-α, -β, and λ). IFN-α induction was TLR9 and MyD88-dependent; a slight impairment was also observed in TLR4 -/- cells. While these responses occurred with purified pDC, IFN-α production was synergistic upon co-culture with myeloid dendritic cells (mDC), an interaction that required direct mDC-pDC contact. L. lactis strains also stimulated expression of immunoregulatory receptors on pDC (ICOS-L and PD-L1), and accordingly augmented pDC induction of CD4 + CD25 + FoxP3 + Treg compared to the Lactobacillus strain. Oral administration of L. lactis JCM5805 induced significant activation of pDC resident in the intestinal draining mesenteric lymph nodes, but not in a remote lymphoid site (spleen). Taken together, certain non-pathogenic spherical LAB in wide dietary use has potent and diverse immunomodulatory effects on pDC potentially relevant to anti-viral immunity and chronic inflammatory disease.

Lactococcus lactis ssp. lactis JCM5805 has been shown to be a rare lactic acid bacterium that can activate plasmacytoid dendritic cells in both murine and human species. In this study, we carried out a randomised placebo-controlled double-blind experiment to evaluate its effect on the pathogenesis of influenza-like illness during the winter season. A total of 213 volunteers were divided into two groups, which received either yogurt made with L. lactis JCM5805 or a placebo beverage daily for 10 weeks. In the JCM5805 group, the cumulative incidence days of 'cough' and 'feverishness', which are defined as major symptoms of an influenza-like illness, were significantly decreased compared with the placebo group. In addition, peripheral blood mononuclear cells prepared from volunteers were cultured in the presence of inactivated human influenza virus A/H1N1 (A/PR/8/34). IFN-α elicited by A/H1N1 tended to be higher in the JCM5805 group compared with the placebo group, and an IFN-α-inducible antiviral factor, interferon-stimulated gene 15 (ISG15), elicited by A/H1N1 was significantly higher in the JCM5805 group compared with the placebo group after the intake period. These results suggest that intake of JCM5805 is able to prevent the pathogenesis of an influenza-like illness via enhancement of an IFN-α-mediated response to the influenza virus.

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When activated by viral infection, plasmacytoid dendritic cells (pDCs) play a primary role in the immune response through secretion of IFN-α. Lactococcus lactis subsp. lactis JCM5805 (JCM5805) is a strain of lactic acid bacteria (LAB) that activates murine and human pDCs to express type I and type III interferons (IFNs). JCM5805 has also been shown to activate pDCs via a Toll-like receptor 9 (TLR9) dependent pathway. In this study, we investigated the anti-viral effects of oral administration of JCM5805 using a mouse model of murine parainfluenza virus (mPIV1) infection. JCM5805-fed mice showed a drastic improvement in survival rate, prevention of weight loss, and reduction in lung histopathology scores compared to control mice. We further examined the mechanism of anti-viral effects elicited by JCM5805 administration using naive mice. Microscopic observations showed that JCM5805 was incorporated into CD11c+ immune cells in Peyer’s patches (PP) and PP pDCs were significantly activated and the expression levels of IFNs were significantly increased. Interestingly, nevertheless resident pDCs at lung were not activated and expressions levels of IFNs at whole lung tissue were not influenced, the expressions of anti-viral factors induced by IFNs, such as Isg15, Oasl2, and Viperin, at lung were up-regulated in JCM5805-fed mice compared to control mice. Therefore expressed IFNs from intestine might be delivered to lung and IFN stimulated genes might be induced. Furthermore, elevated expressions of type I IFNs from lung lymphocytes were observed in response to mPIV1 ex vivo stimulation in JCM5805-fed mice compared to control. This might be due to increased ratio of pDCs located in lung were significantly increased in JCM5805 group. Taken together, a specific LAB strain might be able to affect anti-viral immunological profile in lung via activation of intestinal pDC leading to enhanced anti-viral phenotype in vivo.

Age-related chronic inflammation is a major risk factor for the incidence and prevalence of age-related diseases, including infectious and neurodegenerative diseases. We previously reported that a lactic acid bacteria, Lactobacillus paracasei KW3110, activated macrophages and suppressed inflammation in mice and humans. In this study, we investigated whether long-term intake of heat-killed L. paracasei KW3110 modulated age-related inflammation and altered the gut microbiota in physiologically aged mice. Compared with age-matched control mice, fecal analyses of gut microbiota revealed that intake of L. paracasei KW3110 mitigated age-related changes of beneficial bacterial composition, including the Bifidobacteriaceae family. L. paracasei KW3110 intake also mitigated age-related immune defects by reducing the prevalence of interferon-gamma (IFN-γ) -producing inflammatory CD4-positive T cells in the lamina propia of the small intestine, and reduced serum levels of proinflammatory cytokines. Furthermore, L. paracasei KW3110 intake suppressed retinal inflammation by reducing proinflammatory cytokine-producing macrophage, and age-related retinal cell loss. Taken together, these findings suggested that L. paracasei KW3110 mitigated age-related chronic inflammation through modulation of gut microbiota composition and immune system functions in aged mice, and also reduced age-related retinal ganglion cell (RGC) loss. Further studies are needed to evaluate the effect in age-related senescent changes of the retina.

Background: Visual display terminals (VDTs) emitting blue light can cause ocular disorders including eye fatigue. Some dietary constituents have been reported to be effective in improving ocular disorders while few clinical studies have been performed. We evaluated the effects of heat-killed Lactobacillus paracasei KW 3110 on improving ocular disorders and symptoms of eye fatigue among healthy human subjects with VDT loads. Methods: In vitro, the effect of L. paracasei KW3110 on blue light-induced human retinal pigment epithelial (ARPE-19) cell damage. For clinical studies, 62 healthy Japanese volunteers of 35 to 45 years of age who had experienced eye fatigue were randomized into two groups and given a placebo or L. paracasei KW3110-containing supplements for eight weeks. The primary endpoint was changes in VDT load-induced eye fatigue as determined by critical flicker frequency four and eight weeks after the start of supplementation. Results: In vitro, blue light-induced human retinal cell death was suppressed with the culture supernatants of cells treated with L. paracasei KW3110. In clinical study, the VDT load-induced reduction of critical flicker frequency tended to be milder in the L. paracasei KW3110 group when compared with the placebo group during the fourth week. Subgroup analysis classified by the degree of eye fatigue showed that the VDT load-induced reduction of critical flicker frequency was significantly better in the high-level eye fatigue subjects from the L. paracasei KW3110 group when compared with the placebo group during the fourth week (p = 0.020). Conclusions: L. paracasei KW3110 suppressed blue light-induced retinal pigment epithelial cell death. In the clinical study, ingestion of L. paracasei KW3110 had a potential to improve eye fatigue induced by VDT loads especially high levels of eye fatigue. However, further studies should be required to show more dependable clinical efficacy of L. paracasei KW3110.

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Age-related macular degeneration and retinitis pigmentosa are leading causes of blindness and share a pathological feature, which is photoreceptor degeneration. To date, the lack of a potential treatment to prevent such diseases has raised great concern. Photoreceptor degeneration can be accelerated by excessive light exposure via an inflammatory response; therefore, anti-inflammatory agents would be candidates to prevent the progress of photoreceptor degeneration. We previously reported that a lactic acid bacterium, Lactobacillus paracasei KW3110 (L. paracasei KW3110), activated macrophages suppressing inflammation in mice and humans. Recently, we also showed that intake of L. paracasei KW3110 could mitigate visual display terminal (VDT) load-induced ocular disorders in humans. However, the biological mechanism of L. paracasei KW3110 to retain visual function remains unclear. In this study, we found that L. paracasei KW3110 activated M2 macrophages inducing anti-inflammatory cytokine interleukin-10 (IL-10) production in vitro using bone marrow-derived M2 macrophages. We also show that IL-10 gene expression was significantly increased in the intestinal immune tissues 6 h after oral administration of L. paracasei KW3110 in vivo. Furthermore, we demonstrated that intake of L. paracasei KW3110 suppressed inflammation and photoreceptor degeneration in a murine model of light-induced retinopathy. These results suggest that L. paracasei KW3110 may have a preventive effect against degrative retinal diseases.