Type 1 diabetes (T1D)–induced osteoporosis is characterized by a predominant suppression of osteoblast number and activity, as well as increased bone marrow adiposity but no change in osteoclast activity. The fundamental mechanisms and alternative anabolic treatments (with few side effects) for T1D bone loss remain undetermined. Recent studies by our laboratory and others indicate that probiotics can benefit bone health. Here, we demonstrate that Lactobacillus reuteri, a probiotic with anti-inflammatory and bone health properties, prevents T1D-induced bone loss and marrow adiposity in mice. We further found that L. reuteri treatment prevented the suppression of Wnt10b in T1D bone. Consistent with a role for attenuated bone Wnt10b expression in T1D osteoporosis, we observed that bone-specific Wnt10b transgenic mice are protected from T1D bone loss. To examine the mechanisms of this protection, we focused on TNF-α, a cytokine up-regulated in T1D that causes suppression of osteoblast Wnt10b expression in vitro. Addition of L. reuteri prevented TNF-α–mediated suppression of Wnt10b and osteoblast maturation markers. Taken together, our findings reveal a mechanism by which T1D causes bone loss and open new avenues for use of probiotics to benefit the bone.

For nearly five decades since its discovery, the role of natural IgG, which pre‐exists in neonates and uninfected individuals, has remained unclear due to the general perception that natural antibodies lack affinity for pathogens. Here, we show for the first time that natural IgG recognizes a spectrum of bacteria through lectins like ficolin and mannose binding lectin (MBL). Infection‐inflammation condition markedly increased the affinity of natural IgG for bacteria associated with ficolins. After opsonization with IgG:ficolin complex, the bacteria were phagocytosed by monocytes via FcγRI. Infection of C3 −/− mice indicated that the natural IgG‐mediated immune complex was formed independently of C3. AID −/− mice lacking IgG were susceptible to infection, unless reconstituted with natural IgG. Thus, we have proven that natural IgG is not quiescent; rather, it plays a vital and immediate role in immune defense. Our findings provide a fresh perspective on natural antibodies, opening new avenues to explore host–microbe interaction. There is a [Have you seen?][1] (November 2013) associated with this Article. [1]: http://dx.doi.org/10.1038/emboj.2013.235

By eliciting inflammatory responses, the human immunosurveillance system notably combats invading pathogens, during which acute phase proteins (CRP and cytokines) are elevated markedly. However, the Pseudomonas aeruginosa is a persistent opportunistic pathogen prevalent at the site of local inflammation, and its acquisition of multiple antibiotic-resistance factors poses grave challenges to patient healthcare management. Using blood samples from infected patients, we demonstrate that P. aeruginosa is effectively killed in the plasma under defined local infection-inflammation condition, where slight acidosis and reduced calcium levels (pH 6.5, 2 mM calcium) typically prevail. We showed that this powerful antimicrobial activity is provoked by crosstalk between two plasma proteins; CRP∶L-ficolin interaction led to communication between the complement classical and lectin pathways from which two amplification events emerged. Assays for C4 deposition, phagocytosis, and protein competition consistently proved the functional significance of the amplification pathways in boosting complement-mediated antimicrobial activity. The infection-inflammation condition induced a 100-fold increase in CRP∶L-ficolin interaction in a pH- and calcium-sensitive manner. We conclude that the infection-induced local inflammatory conditions trigger a strong interaction between CRP∶L-ficolin, eliciting complement-amplification pathways which are autonomous and which co-exist with and reinforce the classical and lectin pathways. Our findings provide new insights into the host immune response to P. aeruginosa infection under pathological conditions and the potential development of new therapeutic strategies against bacterial infection. An opportunistic pathogen, Pseudomonas aeruginosa causes local inflammation in various tissues and is an important cause of hospital-acquired infections. While this may manifest as a hot-tub rash, failure to limit such localized inflammation may cause life-threatening septic shock to ensue, leading to multiple organ failure and possibly death. Effective treatment with antibiotics is complicated by the increasing prevalence of multidrug-resistant P. aeruginosa. In this study, we demonstrated that under typical local infection-inflammation conditions of slight acidosis and reduced calcium levels in the blood, P. aeruginosa is killed effectively. This is because such a milieu provokes crosstalk between two proteins involved in host defense, CRP and L-ficolin, which triggers communication between antimicrobial complement pathways that were previously presumed independent of each other. The CRP∶L-ficolin interaction amplifies their antimicrobial activity and enhances bacterial clearance. Insights gained from this host–pathogen interaction mechanism offer fresh perspectives on the potential development of complement immune therapies to enhance eradication of the invading pathogen.

Diabetes affects over 25 million people and is characterized by hyperglycemia resulting from a lack of insulin or reduced insulin sensitivity. A serious complication of diabetes is the increase in fracture risk observed in both type 1 and type 2 diabetic patients. This review focuses on some of the cellular and mechanistic causes of diabetes-induced fracture risk. Type 1 and type 2 diabetes most likely have unique and overlapping mechanisms of bone loss. While type 1 diabetes is associated with reduced bone mineral density, this is not usually seen in type 2 diabetes. Hyperglycemia, present in both type 1 and 2 diabetes, alters bone matrix proteins such as collagen I through nonenzymatic glycation, which can decrease bone toughness and increase fracture risk even in the absence of bone loss. Diabetes is also associated with increased inflammation and altered adipokine and calcitrophic hormone levels, which further contribute to bone pathophysiology. As medical advances significantly lengthen patient lifespan, exposure to diabetic conditions increases and correspondingly so do disease complications. Further research to identify molecular pathways in diabetes-associated bone pathology will provide the basis for therapeutic targets/directions to increase treatment options and improve patient health and well-being.

Although transmembrane C-type lectins (CLs) are known to initiate immune signaling, the participation and mechanism of action of soluble CLs have remained enigmatic. In this study, we found that M-ficolin, a conserved soluble CL of monocyte origin, overcomes its lack of membrane-anchor domain by docking constitutively onto a monocyte transmembrane receptor, G protein-coupled receptor 43 (GPCR43), to form a pathogen sensor-cum-signal transducer. On encountering microbial invaders, the M-ficolin–GPCR43 complex activates the NF-κB cascade to upregulate IL-8 production. We showed that mild acidosis at the local site of infection induces conformational changes in the M-ficolin molecule, which provokes a strong interaction between the C-reactive protein (CRP) and the M-ficolin–GPCR43 complex. The collaboration among CRP–M-ficolin–GPCR43 under acidosis curtails IL-8 production thus preventing immune overactivation. Therefore, we propose that a soluble CL may become membrane-associated through interaction with a transmembrane protein, whereupon infection collaborates with other plasma protein to transduce the infection signal and regulate host defense. Our finding implies a possible mechanism whereby the host might expand its repertoire of immune recognition-cum-regulation tactics by promiscuous protein networking. Furthermore, our identification of the pH-sensitive interfaces of M-ficolin–CRP provides a powerful template for future design of potential immunomodulators.