Immunity & Ageing最新文献

Natural killer (NK) cells are crucial innate immune cells that provide defense against viruses and tumors. However, aging is associated with alterations in NK cell composition and compromised cell functions. Melatonin, known for its anti-tumor effects, has been reported to improve NK cell function. However, the molecular mechanism underlying melatonin's effect on senescent NK cells remains unclear. In this study, we aimed to elucidate the mechanism by which melatonin enhances the function of senescent NK cells. Our findings revealed that melatonin significantly increased the number and function of NK cells in aging mice. The results suggest that melatonin enhances NK cell proliferation, degranulation, and IFN-γ secretion. Further investigations demonstrated that melatonin promotes NK cell maturation and activation, mainly via the JAK3/STAT5 signaling pathway, leading to increased expression of T-bet. These discoveries provide a theoretical basis for potential immunotherapy strategies based on melatonin-mediated modulation of NK cell function in aging individuals.

Background: Aging is a complex biological process characterized by obesity and immunosenescence throughout the organism. Immunosenescence involves a decline in immune function and the increase in chronic-low grade inflammation, called inflammaging. Adipose tissue expansion, particularly that of visceral adipose tissue (VAT), is associated with an increase in pro-inflammatory macrophages that play an important role in modulating immune responses and producing inflammatory cytokines. The leukotriene B4 receptor 1 (BLT1) is a regulator of obesity-induced inflammation. Its ligand, LTB4, acts as a chemoattractant for immune cells and induces inflammation. Studies have shown that BLT1 is crucial for cytokine production during lipopolysaccharide (LPS) endotoxemia challenge in younger organisms. However, the expression patterns and function of BLT1 in older organisms remains unknown.

Results: In this study, we investigated BLT1 expression in immune cell subsets within the VAT of aged male and female mice. Moreover, we examined how antagonizing BLT1 signaling could alter the inflammatory response to LPS in aged mice. Our results demonstrate that aged mice exhibit increased adiposity and inflammation, characterized by elevated frequencies of B and T cells, along with pro-inflammatory macrophages in VAT. BLT1 expression is the highest in VAT macrophages. LPS and LTB4 treatment result in increased BLT1 in young and aged bone marrow-derived macrophages (BMDMs). However, LTB4 treatment resulted in amplified Il6 from aged, but not young BMDMs. Treatment of aged mice with the BLT1 antagonist, U75302, followed by LPS-induced endotoxemia resulted in an increase in anti-inflammatory macrophages, reduced phosphorylated NFκB and reduced Il6.

Conclusions: This study provides valuable insights into the age- and sex- specific changes in BLT1 expression on immune cell subsets within VAT. This study offers support for the potential of BLT1 in modulating inflammation in aging.

Background: Mouse brains can contain specific polyglucosan aggregates known as Periodic Acid-Schiff (PAS)-granules. Generated in astrocytes, these granules increase with age and exhibit neo-epitopes of carbohydrate nature that are recognized by natural IgM antibodies (IgMs). The existence of neoepitopes on PAS granules suggests the presence of neoepitopes in other brain structures, and this is investigated here. To this end, brain sections from SAMP8 and ICR-CD1 mice were examined at different ages.

Results: We have identified two novel structures that, apart from PAS granules, are recognized by natural IgMs. On one side, IgM reactive (IgM⁺) granular structures which are placed in the longitudinal fissure, the quadrigeminal cistern, and a region that extends from the quadrigeminal cistern to the interpeduncular cistern. This last region, located between the telencephalon and both the mesencephalon and diencephalon, is designated henceforth as the fissura magna, as it is indeed a fissure and the largest in the brain. As all these regions are extraparenchymal (EP), the IgM⁺ granules found in these zones have been named EP granules. These EP granules are mainly associated with fibroblasts and are not stained with PAS. On the other side, some IgM⁺ astrocytes have been found in the glia limitans, near the above-mentioned fissures. Remarkably, EP granules are more prevalent at younger ages, while the number of IgM⁺ astrocytes increases with age, similarly to the already described evolution of PAS granules.

Conclusions: The present work reports the presence of two brain-related structures that, apart from PAS granules, contain neo-epitopes of carbohydrate nature, namely EP granules and IgM⁺ astrocytes. We suggest that EP granules, associated to fibroblasts, may be part of a physiological function in brain clearance or brain-CSF immune surveillance, while both PAS granules and IgM⁺ astrocytes may be related to the increasing accumulation of harmful materials that occurs with age and linked to brain protective mechanisms. Moreover, the specific localisation of these EP granules and IgM⁺ astrocytes suggest the importance of the fissura magna in these brain-related cleaning and immune functions. The overall results reinforce the possible link between the fissura magna and the functioning of the glymphatic system.

Sarcopenia is a complex age-associated syndrome of progressive loss of muscle mass and strength. Although this condition is influenced by many factors, age-related changes in immune function including immune cell dynamics, and chronic inflammation contribute to its progression. The complex interplay between the immune system, gut-muscle axis, and autophagy further underscores their important roles in sarcopenia pathogenesis. Immunomodulation has emerged as a promising strategy to counteract sarcopenia. Traditional management approaches to treat sarcopenia including physical exercise and nutritional supplementation, and the emerging technologies of biophysical stimulation demonstrated the importance of immunomodulation and regulation of macrophages and T cells and reduction of chronic inflammation. Treatments to alleviate low-grade inflammation in older adults by modulating gut microbial composition and diversity further combat sarcopenia. Furthermore, some pharmacological interventions, nano-medicine, and cell therapies targeting muscle, gut microbiota, or autophagy present additional avenues for immunomodulation in sarcopenia. This narrative review explores the immunological underpinnings of sarcopenia, elucidating the relationship between the immune system and muscle during ageing. Additionally, the review discusses new areas such as the gut-muscle axis and autophagy, which bridge immune system function and muscle health. Insights into current and potential approaches for sarcopenia management through modulation of the immune system are provided, along with suggestions for future research directions and therapeutic strategies. We aim to guide further investigation into clinical immunological biomarkers and identify indicators for sarcopenia diagnosis and potential treatment targets to combat this condition. We also aim to draw attention to the importance of considering immunomodulation in the clinical management of sarcopenia.

B-1 cells have intricate biology, with distinct function, phenotype and developmental origin from conventional B cells. They generate a B cell receptor with conserved germline characteristics and biased V(D)J recombination, allowing this innate-like lymphocyte to spontaneously produce self-reactive natural antibodies (NAbs) and become activated by immune stimuli in a T cell-independent manner. NAbs were suggested as "rheostats" for the chronic diseases in advanced age. In fact, age-dependent loss of function of NAbs has been associated with clinically-relevant diseases in the elderly, such as atherosclerosis and neurodegenerative disorders. Here, we analyzed comprehensively the ontogeny, phenotypic characteristics, functional properties and emerging roles of B-1 cells and NAbs in health and disease. Additionally, after navigating through the complexities of B-1 cell biology from development to aging, therapeutic opportunities in the field are discussed.

Background: Proteostasis is a critical aging hallmark responsible for removing damaged or misfolded proteins and their aggregates by improving proteasomal degradation through the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS). Research on the impact of heat-killed probiotic bacteria and their structural components on aging hallmarks and innate immune responses is scarce, yet enhancing these effects could potentially delay age-related diseases.

Results: This study introduces a novel heat-killed Levilactobacillus brevis strain MKAK9 (HK MKAK9), along with its exopolysaccharide (EPS), demonstrating their ability to extend longevity by improving proteostasis and immune responses in wild-type Caenorhabditis elegans. We elucidate the underlying mechanisms through a comprehensive approach involving mRNA- and small RNA sequencing, proteomic analysis, lifespan assays on loss-of-function mutants, and quantitative RT-PCR. Mechanistically, HK MKAK9 and its EPS resulted in downregulation of the insulin-like signaling pathway in a DAF-16-dependent manner, enhancing protein ubiquitination and subsequent proteasomal degradation through activation of the ALP pathway, which is partially mediated by microRNA mir-243. Importantly, autophagosomes engulf ubiquitinylated proteins, as evidenced by increased expression of the autophagy receptor sqst-3, and subsequently fuse with lysosomes, facilitated by increased levels of the lysosome-associated membrane protein (LAMP) lmp-1, suggesting the formation of autolysosomes for degradation of the selected cargo. Moreover, HK MKAK9 and its EPS activated the p38 MAPK pathway and its downstream SKN-1 transcription factor, which are known to regulate genes involved in innate immune response (thn-1, ilys-1, cnc-2, spp-9, spp-21, clec-47, and clec-266) and antioxidation (sod-3 and gst-44), thereby reducing the accumulation of reactive oxygen species (ROS) at both cellular and mitochondrial levels. Notably, SOD-3 emerged as a transcriptional target of both DAF-16 and SKN-1 transcription factors.

Conclusion: Our research sets a benchmark for future investigations by demonstrating that heat-killed probiotic and its specific cellular component, EPS, can downregulate the insulin-signaling pathway, potentially improving the autophagy-lysosome pathway (ALP) for degrading ubiquitinylated proteins and promoting organismal longevity. Additionally, we discovered that increased expression of microRNA mir-243 regulates insulin-like signaling and its downstream ALP pathway. Our findings also indicate that postbiotic treatment may bolster antioxidative and innate immune responses, offering a promising avenue for interventions in aging-related diseases.