Interleukin-10 plays important, yet contrasting, roles in host protection against bacterial infections and in the septic response. To determine the role of IL-10 in the host defense against Acinetobacter baumannii infection, wild-type (WT) and IL-10-deficient mice were infected intranasally with the bacteria. IL-10-deficient mice exhibited increased mortality, severe pathology, and excess production of proinflammatory cytokines and chemokines in the lungs, and increased bacterial burdens in bronchoalveolar lavage (BAL) fluids and lung homogenates after A. baumannii infection, compared to WT mice. Intranasal administration of recombinant IL-10 rescued mice from the lethality of the bacterial infection by promoting bacterial clearance and reducing production of cytokines and chemokines in the lungs. In vitro experiments revealed that IL-10 enhanced phagocytosis and bacterial killing by macrophages by upregulating the macrophage receptor with collagenous structure (MARCO). In addition, A. baumannii-induced activation of STAT3 was impaired in IL-10-deficient macrophages, which was essential for expression of MARCO. Intranasal adoptive transfer of WT macrophages resulted in significant increases in mice survival and bacterial clearance in IL-10-deficient mice infected with A. baumannii. Our results show that IL-10 played an important role in the host defense against pulmonary infection of A. baumannii by promoting the antibacterial function of macrophages by regulating MARCO expression through the STAT3-mediated pathway.

Helicobacter pylori is a gram-negative, microaerophilic, and spiral-shaped bacterium and causes gastrointestinal diseases in human. IL-1β is a representative cytokine produced in innate immune cells and is considered to be a key factor in the development of gastrointestinal malignancies. However, the mechanism of IL-1β production by neutrophils during H. pylori infection is still unknown. We designed this study to identify host and bacterial factors involved in regulation of H. pylori-induced IL-1β production in neutrophils. We found that H. pylori-induced IL-1β production is abolished in NLRP3-, ASC-, and caspase-1/11-deficient neutrophils, suggesting essential role for NLRP3 inflammasome in IL-1β response against H. pylori. Host TLR2, but not TLR4 and Nod2, was also required for transcription of NLRP3 and IL-1β as well as secretion of IL-1β. H. pylori lacking cagL, a key component of the type IV secretion system (T4SS), induced less IL-1β production in neutrophils than did its isogenic WT strain, whereas vacA and ureA were dispensable. Moreover, T4SS was involved in caspase-1 activation and IL-1β maturation in H. pylori-infected neutrophils. We also found that FlaA is essential for H. pylori-mediated IL-1β production in neutrophils, but not dendritic cells. TLR5 and NLRC4 were not required for H. pylori-induced IL-1β production in neutrophils. Instead, bacterial motility is essential for the production of IL-1β in response to H. pylori. In conclusion, our study shows that host TLR2 and NLRP3 inflammasome and bacterial T4SS and motility are essential factors for IL-1β production by neutrophils in response to H. pylori.

This study was conducted to investigate the inhibitory effects of the cell‐free culture supernatant of Lactobacillus curvatus Wikim 38 (LC38‐CS) on RANKL‐induced osteoclast differentiation and bone loss in a mice model of ovariectomy‐induced post‐menopausal osteoporosis. LC38‐CS inhibited the RANKL‐induced differentiation of bone marrow‐derived macrophages (BMDMs) into osteoclasts in a dose‐dependent manner. F‐actin ring formation and bone resorption were also reduced by LC38‐CS treatment of RANKL‐treated BMDMs. In addition, LC38‐CS decreased the RANKL‐induced activation of the TRAF6/NF‐κB/MAPKs axis at the early stage and the expression of osteoclastogenesis‐related genes in BMDMs treated with RANKL. PRMT1 and ADMA levels, new biomarkers for osteoclastogenesis, were decreased by LC38‐CS treatment. The administration of LC38‐CS increased bone volume and bone mineral density in ovariectomized mice in μ‐CT analysis. These findings suggest that LC38‐CS inhibited RANKL‐induced osteoclast differentiation by the downregulation of molecular mechanisms and exerted anti‐osteoporotic effects.

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Mycobacterium abscessus (MAB) is one of the rapidly growing, multidrug-resistant non-tuberculous mycobacteria (NTM) causing various diseases including pulmonary disorder. Although it has been known that type I interferons (IFNs) contribute to host defense against bacterial infections, the role of type I IFNs against MAB infection is still unclear. In the present study, we show that rIFN-β treatment reduced the intracellular growth of MAB in macrophages. Deficiency of IFN-α/β receptor (IFNAR) led to the reduction of nitric oxide (NO) production in MAB-infected macrophages. Consistently, rIFN-β treatment enhanced the expression of iNOS gene and protein, and NO production in response to MAB. We also found that NO is essential for the intracellular growth control of MAB within macrophages in an inhibitor assay using iNOS-deficient cells. In addition, pretreatment of rIFN-β before MAB infection in mice increased production of NO in the lungs at day 1 after infection and promoted the bacterial clearance at day 5. However, when alveolar macrophages were depleted by treatment of clodronate liposome, rIFN-β did not promote the bacterial clearance in the lungs. Moreover, we found that a cytosolic receptor nucleotide-binding oligomerization domain 2 (NOD2) is required for MAB-induced TANK binding kinase 1 (TBK1) phosphorylation and IFN-β gene expression in macrophages. Finally, increase in the bacterial loads caused by reduction of NO levels was reversed by rIFN-β treatment in the lungs of NOD2-deficient mice. Collectively, our findings suggest that type I IFNs act as an intermediator of NOD2-induced NO production in macrophages and thus contribute to host defense against MAB infection.