Mycoketide: A CD1c-Presented Antigen with Important Implications in Mycobacterial Infection

Mycobacterium tuberculosis and related mycobacteria species are unique in that the acid-fast bacilli possess a highly lipid-rich cell wall that not simply confers resistance to treatment with acid alcohol, but also controls their survival and virulence. It has recently been established that a fraction of the cell wall lipid components of mycobacteria can function as antigens targeted by the acquired immunity of the host. Human group 1 CD1 molecules (CD1a, CD1b, and CD1c) bind a pool of lipid antigens expressed by mycobacteria and present them to specific T cells, thereby mediating an effective pathway for host defense against tuberculosis. The contrasting and mutually complementary functions of CD1a and CD1b molecules in terms of the repertoire of antigens they bind have been well appreciated, but it remains to be established how CD1c may play a unique role. Nevertheless, recent advances in our understanding of the CD1c structure as well as the biosynthetic pathway of a CD1c-presented antigen, mannose-1, β-phosphomycoketide, expressed by pathogenic mycobacteria now unravel a new aspect of the group 1 CD1 biology that has not been appreciated in previous studies of CD1a and CD1b molecules

Naringenin suppresses neutrophil infiltration into adipose tissue in high-fat diet-induced obese mice

Recruitment of immune cells to adipose tissue is altered dramatically in obesity, which results in chronic inflammation ofthe adipose tissue that leads to metabolic disorders, such as insulin resistance and type 2 diabetes mellitus. The regulationof immune cell infiltration into adipose tissue has prophylactic and therapeutic implications for obesity-related diseases. Wepreviously showed that naringenin, a citrus flavonoid, suppressed macrophage infiltration into adipose tissue by inhibitingmonocyte chemoattractant protein-1 (MCP-1) expression in the progression phase to high-fat diet (HFD)-induced obesity.In the current study, we evaluated the effects of naringenin on neutrophil infiltration into adipose tissue, because neutrophilsalso infiltrate into adipose tissue in the progression phase to obesity. Naringenin suppressed neutrophil infiltration into adiposetissue induced by the short-term (2 weeks) feeding of a HFD to mice. Naringenin tended to inhibit the HFD-inducedexpression of several chemokines, including MCP-1 and MCP-3, in adipose tissue. Naringenin also inhibited MCP-3 expressionin 3T3-L1 adipocytes and a co-culture of 3T3-L1 adipocytes and RAW264 macrophages. However, naringenin did notaffect the expression of macrophage inflammatory protein-2 (MIP-2), an important chemokine for neutrophil migration andactivation, in macrophages or in a co-culture of adipocytes and macrophages. Our results suggest that naringenin suppressesneutrophil infiltration into adipose tissue via the regulation of MCP-3 expression and macrophage infiltration.九州保健福祉大学201

Mycoketide: A CD1c-Presented Antigen with Important Implications in Mycobacterial Infection

Mycobacterium tuberculosis and related mycobacteria species are unique in that the acid-fast bacilli possess a highly lipid-rich cell wall that not simply confers resistance to treatment with acid alcohol, but also controls their survival and virulence. It has recently been established that a fraction of the cell wall lipid components of mycobacteria can function as antigens targeted by the acquired immunity of the host. Human group 1 CD1 molecules (CD1a, CD1b, and CD1c) bind a pool of lipid antigens expressed by mycobacteria and present them to specific T cells, thereby mediating an effective pathway for host defense against tuberculosis. The contrasting and mutually complementary functions of CD1a and CD1b molecules in terms of the repertoire of antigens they bind have been well appreciated, but it remains to be established how CD1c may play a unique role. Nevertheless, recent advances in our understanding of the CD1c structure as well as the biosynthetic pathway of a CD1c-presented antigen, mannose-1, β-phosphomycoketide, expressed by pathogenic mycobacteria now unravel a new aspect of the group 1 CD1 biology that has not been appreciated in previous studies of CD1a and CD1b molecules

Effect of oral tranexamic acid on macular edema associated with retinal vein occlusion or diabetes

Purpose: Tranexamic acid (TXA) is a widely used antifibrinolytic agent that can also cause a decrease in vascular permeability. We hypothesized that TXA could improve macular edema (ME) that is caused by an increase in retinal vascular permeability. The aim of this study is to evaluate the efficacy of oral TXA for ME associated with retinal vein occlusion (RVO) or diabetic ME (DME).Patients and methods: Oral TXA (1,500 mg daily for 2 weeks) was administered to patients with persistent ME secondary to RVO (7 eyes) and DME (7 eyes). After 2 weeks (ie, the final day of administration) and 6 weeks (ie, 4 weeks after the final administration), best-corrected visual acuity and central macular thickness (CMT) were measured and compared with baseline. Analyses were performed for RVO and DME cases. No other treatment was performed during the study period.Results: In RVO cases, significant improvement in CMT was found between baseline (467.7±121.4 µm) and 2-week measurements after treatment (428.7±110.5 µm, p=0.024). No significant change was found in CMT between measurements taken at baseline and 6 weeks after treatment. In DME cases, no significant change was found in CMT between measurements taken at baseline and 2 or 6 weeks after treatment. In all analyses of best-corrected visual acuity, no significant change was observed.Conclusion: The results support the hypothesis that plasmin plays a role in the development of ME associated with RVO, and oral TXA administration may be useful as an adjuvant treatment when combined with other agents such as anti-vascular endothelial growth factor

A New Navigation System for Minimally Invasive Total Knee Arthroplasty

A computer-assisted navigation system to be used for total knee arthroplasties (TKAs) was reported to improve the accuracy of bone resection and result in precise implant placement, but the concomitant surgical invasion and time consumption are clinical problems. We developed a computed tomography (CT)-based navigation system (NNS) to be used for minimally invasive TKA. It requires only the reference points from a small limited area of the medial femoral condyle and proximal tibia through a skin incision to obtain optical images. Here we evaluated the usefulness and accuracy of the NNS in comparison with the commercially available BrainLAB image-free navigation system (BLS). In a clinical experiment, the registration times obtained with the NNS tended to be shorter than those obtained with the BLS, but not significantly so. The NNS group tended to be in the extended position in the sagittal plane of the distal femur within 3 degrees, and the BLS group showed rather flexed deviation in the sagittal plane of the anterior femur

Separate Pathways for Antigen Presentation by CD1 Molecules

AbstractThe ability to sample relevant intracellular compartments is necessary for effective antigen presentation. To detect peptide antigens, MHC class I and II molecules differentially sample cytosolic and endosomal compartments. CD1 constitutes another lineage of lipid antigen-presenting molecules. We show that CD1b traffics deeply into late endosomal compartments, while CD1a is excluded from these compartments and instead traffics independently in the recycling pathway of the early endocytic system. Further, CD1b but not CD1a antigen presentation is dependent upon vesicular acidification. Since lipids and various bacteria are known to traffic differentially, either penetrating deeply into the endocytic system or following the route of recycling endosomes, these findings elucidate efficient monitoring of distinct components of the endocytic compartment by CD1 lipid antigen-presenting molecules

CD1-mediated γ/δ T Cell Maturation of Dendritic Cells

Immature myeloid dendritic cells (DCs) express only low levels of major histocompatibility complex (MHC) class II but express high levels of CD1 a, b, and c antigen-presenting molecules at the cell surface. As Vδ1+ γ/δ T cells are the main tissue subset of γ/δ T cells and they are known to recognize CD1c in the absence of specific foreign antigen recognition, we examined the possible interaction of these T cells with immature DCs. We show that CD1-restricted γ/δ T cells can mediate the maturation of DCs. DC maturation required cell–cell contact and could be blocked by antibodies against CD1c. The maturation process was partially mediated by tumor necrosis factor α. Importantly, immature DCs matured in the presence of lipopolysaccharide and CD1-restricted γ/δ T cells produced bioactive interleukin-12p70. In addition, these DCs were able to efficiently present peptide antigens to naive CD4+ T cells. CD1-restricted γ/δ T cell recognition of immature DCs provides the human immune system with the capacity to rapidly generate a pool of mature DCs early during microbial invasion. This may be an important source of critical host signals for T helper type 1 polarization of antigen-specific naive T cells and the subsequent adaptive immune response

Effect of inactivated Streptococcus pneumoniae as non-pathogenic particles on the severity of pneumonia caused by respiratory syncytial virus infection in mice

The severity of pneumonia in respiratory syncytial virus (RSV) infection is strongly related to hostimmune response and external factors such as bacteria and environmental chemicals. Weinvestigated the effect of inactivated Streptococcus pneumoniae (ISP) as non-pathogenic particleson the severity of pneumonia in RSV-infected mice. Mice were intranasally exposed to ISP beforeRSV infection. On day 5 post-infection, we examined the lung tissues, virus titer, and infiltratedcells in the lungs. The ISP did not cause significant histopathological effects on lungs of RSVinfectedmice and reduced virus titer in the lungs. It reduced the ratio of lymphocyte infiltrationinto the lungs and consequently the ratio of macrophage increased. In addition, we found that ISPincreased RANTES level in bronchoalveolar lavage fluid from RSV-infected mice on day 1 postinfection,but reduced type I interferon levels. Thus, ISP did not exacerbate pneumonia in RSVinfection; rather, it might mildly reduce the severity. We characterize and discuss the inherentactivity of ISP as non-pathogenic particles inducing the role of RANTES on the pneumonia in RSVinfection.九州保健福祉大学201

Neutrophil S100A9 supports M2 macrophage niche formation in granulomas

慢性炎症「肉芽腫」における好中球の新しい炎症制御系の解明 --M2マクロファージの新たな誘導メカニズム解明--. 京都大学プレスリリース. 2023-02-17.In search of inflammatory Achilles heel. 京都大学プレスリリース. 2023-03-10.Mycobacterium infection gives rise to granulomas predominantly composed of inflammatory M1-like macrophages, with bacteria-permissive M2 macrophages also detected in deep granulomas. Our histological analysis of Mycobacterium bovis bacillus Calmette-Guerin-elicited granulomas in guinea pigs revealed that S100A9-expressing neutrophils bordered a unique M2 niche within the inner circle of concentrically multilayered granulomas. We evaluated the effect of S100A9 on macrophage M2 polarization based on guinea pig studies. S100A9-deficient mouse neutrophils abrogated M2 polarization, which was critically dependent on COX-2 signaling in neutrophils. Mechanistic evidence suggested that nuclear S100A9 interacts with C/EBPβ, which cooperatively activates the Cox-2 promoter and amplifies prostaglandin E2 production, followed by M2 polarization in proximal macrophages. Because the M2 populations in guinea pig granulomas were abolished via treatment with celecoxib, a selective COX-2 inhibitor, we propose the S100A9/Cox-2 axis as a major pathway driving M2 niche formation in granulomas

Murine CD1d-Restricted T Cell Recognition of Cellular Lipids

AbstractNKT cells are associated with immunological control of autoimmune disease and cancer and can recognize cell surface mCD1d without addition of exogenous antigens. Cellular antigens presented by mCD1d have not been identified, although NKT cells can recognize a synthetic glycolipid, α-GalCer. Here we show that after addition of a lipid extract from a tumor cell line, plate-bound mCD1d molecules stimulated an NKT cell hybridoma. This hybridoma also responded strongly to three purified phospholipids, but failed to recognize α-GalCer. Seven of sixteen other mCD1d restricted hybridomas also showed a response to certain purified phospholipids. These findings suggest NKT cells can recognize cellular antigens distinct from α-GalCer and identify phospholipids as potential self-antigens presented by mCD1d