The role of the immune system in osteoarthritis: mechanisms, challenges and future directions
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Type 2 immunity in allergic diseases
Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis (EoE), food and drug allergies, and atopic dermatitis (AD). Type 2 immunity has evolved to protect against parasitic diseases and toxins, plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body, maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects. During the development of a type 2 immune response, an innate immune response initiates starting from epithelial cells and innate lymphoid cells (ILCs), including dendritic cells and macrophages, and translates to adaptive T and B-cell immunity, particularly IgE antibody production. Eosinophils, mast cells and basophils have effects on effector functions. Cytokines from ILC2s and CD4+ helper type 2 (Th2) cells, CD8 + T cells, and NK-T cells, along with myeloid cells, including IL-4, IL-5, IL-9, and IL-13, initiate and sustain allergic inflammation via T cell cells, eosinophils, and ILC2s; promote IgE class switching; and open the epithelial barrier. Epithelial cell activation, alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases. Recent biologics targeting the pathways and effector functions of IL4/IL13, IL-5, and IgE have shown promising results for almost all ages, although some patients with severe allergic diseases do not respond to these therapies, highlighting the unmet need for a more detailed and personalized approach.
Effect of regional crosstalk between sympathetic nerves and sensory nerves on temporomandibular joint osteoarthritic pain
Temporomandibular joint osteoarthritis (TMJ-OA) is a common disease often accompanied by pain, seriously affecting physical and mental health of patients. Abnormal innervation at the osteochondral junction has been considered as a predominant origin of arthralgia, while the specific mechanism mediating pain remains unclear. To investigate the underlying mechanism of TMJ-OA pain, an abnormal joint loading model was used to induce TMJ-OA pain. We found that during the development of TMJ-OA, the increased innervation of sympathetic nerve of subchondral bone precedes that of sensory nerves. Furthermore, these two types of nerves are spatially closely associated. Additionally, it was discovered that activation of sympathetic neural signals promotes osteoarthritic pain in mice, whereas blocking these signals effectively alleviates pain. In vitro experiments also confirmed that norepinephrine released by sympathetic neurons promotes the activation and axonal growth of sensory neurons. Moreover, we also discovered that through releasing norepinephrine, regional sympathetic nerves of subchondral bone were found to regulate growth and activation of local sensory nerves synergistically with other pain regulators. This study identified the role of regional sympathetic nerves in mediating pain in TMJ-OA. It sheds light on a new mechanism of abnormal innervation at the osteochondral junction and the regional crosstalk between peripheral nerves, providing a potential target for treating TMJ-OA pain.
Engineering bone/cartilage organoids: strategy, progress, and application
The concept and development of bone/cartilage organoids are rapidly gaining momentum, providing opportunities for both fundamental and translational research in bone biology. Bone/cartilage organoids, essentially miniature bone/cartilage tissues grown in vitro, enable the study of complex cellular interactions, biological processes, and disease pathology in a representative and controlled environment. This review provides a comprehensive and up-to-date overview of the field, focusing on the strategies for bone/cartilage organoid construction strategies, progresses in the research, and potential applications. We delve into the significance of selecting appropriate cells, matrix gels, cytokines/inducers, and construction techniques. Moreover, we explore the role of bone/cartilage organoids in advancing our understanding of bone/cartilage reconstruction, disease modeling, drug screening, disease prevention, and treatment strategies. While acknowledging the potential of these organoids, we discuss the inherent challenges and limitations in the field and propose potential solutions, including the use of bioprinting for organoid induction, AI for improved screening processes, and the exploration of assembloids for more complex, multicellular bone/cartilage organoids models. We believe that with continuous refinement and standardization, bone/cartilage organoids can profoundly impact patient-specific therapeutic interventions and lead the way in regenerative medicine.
Nonenzymatic lysine d-lactylation induced by glyoxalase II substrate SLG dampens inflammatory immune responses
Immunometabolism is critical in the regulation of immunity and inflammation; however, the mechanism of preventing aberrant activation-induced immunopathology remains largely unclear. Here, we report that glyoxalase II (GLO2) in the glycolysis branching pathway is specifically downregulated by NF-κB signaling during innate immune activation via tristetraprolin (TTP)-mediated mRNA decay. As a result, its substrate S-D-lactoylglutathione (SLG) accumulates in the cytosol and directly induces d-lactyllysine modification of proteins. This nonenzymatic lactylation by SLG is greatly facilitated by a nearby cysteine residue, as it initially reacts with SLG to form a reversible S-lactylated thiol intermediate, followed by SN-transfer of the lactyl moiety to a proximal lysine. Lactylome profiling identifies 2255 lactylation sites mostly in cytosolic proteins of activated macrophages, and global protein structure analysis suggests that proximity to a cysteine residue determines the susceptibility of lysine to SLG-mediated d-lactylation. Furthermore, lactylation is preferentially enriched in proteins involved in immune activation and inflammatory pathways, and d-lactylation at lysine 310 (K310) of RelA attenuates inflammatory signaling and NF-κB transcriptional activity to restore immune homeostasis. Accordingly, TTP-binding site mutation or overexpression of GLO2 in vivo blocks this feedback lactylation in innate immune cells and promotes inflammation, whereas genetic deficiency or pharmacological inhibition of GLO2 restricts immune activation and attenuates inflammatory immunopathology both in vitro and in vivo. Importantly, dysregulation of the GLO2/SLG/d-lactylation regulatory axis is closely associated with human inflammatory phenotypes. Overall, our findings uncover an immunometabolic feedback loop of SLG-induced nonenzymatic d-lactylation and implicate GLO2 as a promising target for combating clinical inflammatory disorders.
Cellular and molecular mechanisms underlying obesity in degenerative spine and joint diseases
Degenerative spine and joint diseases, including intervertebral disc degeneration (IDD), ossification of the spinal ligaments (OSL), and osteoarthritis (OA), are common musculoskeletal diseases that cause pain or disability to the patients. However, the pathogenesis of these musculoskeletal disorders is complex and has not been elucidated clearly to date. As a matter of fact, the spine and joints are not independent of other organs and tissues. Recently, accumulating evidence demonstrates the association between obesity and degenerative musculoskeletal diseases. Obesity is a common metabolic disease characterized by excessive adipose tissue or abnormal adipose distribution in the body. Excessive mechanical stress is regarded as a critical risk factor for obesity-related pathology. Additionally, obesity-related factors, mainly including lipid metabolism disorder, dysregulated pro-inflammatory adipokines and cytokines, are reported as plausible links between obesity and various human diseases. Importantly, these obesity-related factors are deeply involved in the regulation of cell phenotypes and cell fates, extracellular matrix (ECM) metabolism, and inflammation in the pathophysiological processes of degenerative spine and joint diseases. In this study, we systematically discuss the potential cellular and molecular mechanisms underlying obesity in these degenerative musculoskeletal diseases, and hope to provide novel insights for developing targeted therapeutic strategies.
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