Understanding Inflammation Regulation Mechanisms

GLP-1-brain-immune axis to control inflammation Known as GLP-1 receptor agonists, for glucagon like peptide 1, these medications mimic the gut hormone GLP1, which regulates blood sugar levels and appetite. Among them are the popular weight loss jabs but similar compounds have been used for more than 18 years to treat type 2 diabetes. Now, the team has focused on teasing out how GLP-1 drugs reduce inflammation, which is a common factor in chronic metabolic diseases. Inflammation is the process by which the immune system recognizes and removes foreign agents such as viruses and bacteria and promotes healing. In chronic form, however, it can persist without an external cause and lead to organ damage. Given that immune cells are embedded within most organs, an obvious assumption was that the drugs dampen inflammation by interacting with GLP-1 receptors on the immune cells. This is the case in the gut, where large numbers of immune cells are activated by GLP-1. But in other organs, the number of immune cells containing GLP-1 receptors is negligible, indicating another mechanism to be at play. For the study, the authors induced systemic inflammation in mice by either injecting them with a bacterial cell wall component or a bacterial slur to induce sepsis, an extensive inflammation throughout the body that leads to organ damage. Remarkably, GLP-1 agonists reduced inflammation, but only when its receptors in the brain were left unblocked. When these brain receptors were pharmacologically inhibited or genetically removed in mice, the drugs’ ability to reduce inflammation was lost. The findings demonstrated for the first time that there is a GLP-1-brain-immune axis that controls inflammation across the body independent of weight loss, even in peripheral organs devoid of GLP1 receptors, said the author. #ScienceMission #sciencenewshighlights https://lnkd.in/g-h7jquh

𝐈𝐋-10 - 𝐓𝐇𝐄 𝐌𝐀𝐒𝐓𝐄𝐑 𝐑𝐄𝐆𝐔𝐋𝐀𝐓𝐎𝐑 𝐎𝐅 𝐈𝐌𝐌𝐔𝐍𝐈𝐓𝐘 𝐓𝐎 𝐈𝐍𝐅𝐄𝐂𝐓𝐈𝐎𝐍 In the realm of immunological research, the work of Kevin N. Couper, Daniel G. Blount, and Eleanor M. Riley, as presented in their illuminating review article titled "IL-10: The Master Regulator of Immunity to Infection" in The Journal of Immunology (2008), stands as a testament to the complex interplay between immune responses and pathogen defense mechanisms. Their comprehensive analysis not only sheds light on the multifaceted role of IL-10 in modulating immune responses but also emphasizes its critical function in maintaining a delicate balance between effective pathogen clearance and the prevention of immune-mediated tissue damage. 𝑰𝑳-10: 𝑨 𝑲𝒆𝒚𝒔𝒕𝒐𝒏𝒆 𝒊𝒏 𝑰𝒎𝒎𝒖𝒏𝒆 𝑹𝒆𝒈𝒖𝒍𝒂𝒕𝒊𝒐𝒏 Interleukin-10 (IL-10) emerges as a central figure in the orchestration of immune responses, adeptly navigating the thin line between necessary aggression against pathogens and the potential for self-destructive immune activation. Originally identified for its role in inhibiting cytokine synthesis in Th1 cells by Th2 cells, IL-10's regulatory scope has since expanded, revealing its production by a variety of cells including macrophages, dendritic cells (DCs), B cells, and T cells. This cytokine's ability to suppress proinflammatory responses while simultaneously facilitating pathogen clearance encapsulates its indispensable role in immune homeostasis. 𝑴𝒆𝒄𝒉𝒂𝒏𝒊𝒔𝒎𝒔 𝒐𝒇 𝑰𝑳-10: 𝑩𝒓𝒊𝒅𝒈𝒊𝒏𝒈 𝑰𝒏𝒏𝒂𝒕𝒆 𝒂𝒏𝒅 𝑨𝒅𝒂𝒑𝒕𝒊𝒗𝒆 𝑰𝒎𝒎𝒖𝒏𝒊𝒕𝒚 IL-10's mechanisms of action are as diverse as the cells that produce it. By directly inhibiting MHC class II and co-stimulatory molecule expression on monocytes and macrophages, IL-10 curtails the production of proinflammatory cytokines and chemokines, thus mitigating the potential for tissue damage. Moreover, its autocrine signaling in DCs can significantly affect chemokine production and trafficking, demonstrating IL-10's profound impact on the recruitment and differentiation of naive T cells. This cytokine exemplifies the intricate interplay between innate and adaptive immune responses, ensuring a coordinated and balanced defense mechanism. 𝑻𝒉𝒆 𝑫𝒖𝒂𝒍 𝑭𝒂𝒄𝒆𝒕𝒔 𝒐𝒇 𝑰𝑳-10 𝑫𝒖𝒓𝒊𝒏𝒈 𝑰𝒏𝒇𝒆𝒄𝒕𝒊𝒐𝒏 The role of IL-10 during infection is a narrative of balance—its timely expression can ameliorate excessive Th1 and CD8+ T cell responses, thereby preventing immunopathology. However, an untimely or excessive IL-10 response can lead to diminished pathogen control. 𝑭𝒐𝒐𝒅 𝒇𝒐𝒓 𝑻𝒉𝒐𝒖𝒈𝒉𝒕: How might future research on IL-10's role in the immune system lead to novel therapeutic strategies that challenge our current understanding of the boundary between immune enhancement and autoimmune risk, potentially reshaping our approach to treating chronic diseases?

Happy Monday all! Check out this open access Immunity paper by Mangani et al., "Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state." Summary: T helper (Th) 17 cells encompass a spectrum of cell states, including cells that maintain homeostatic tissue functions and pro-inflammatory cells that can drive autoimmune tissue damage. Identifying regulators that determine Th17 cell states can identify ways to control tissue inflammation and restore homeostasis. Here, we found that interleukin (IL)-23, a cytokine critical for inducing pro-inflammatory Th17 cells, decreased transcription factor T cell factor 1 (TCF1) expression. Conditional deletion of TCF1 in mature T cells increased the pro-inflammatory potential of Th17 cells, even in the absence of IL-23 receptor signaling, and conferred pro-inflammatory potential to homeostatic Th17 cells. Conversely, sustained TCF1 expression decreased pro-inflammatory Th17 potential. Mechanistically, TCF1 bound to RORγt, thereby interfering with its pro-inflammatory functions, and orchestrated a regulatory network that determined Th17 cell state. Our findings identify TCF1 as a major determinant of Th17 cell state and provide important insight for the development of therapies for Th17-driven inflammatory diseases. #drugdiscovery #tcelltherapy #inflammation #immunology #scientificresearch

Light targets cells for death and triggers immune response with laser precision. New method of precisely targeting troublesome cells for death using light could unlock understanding of and treatments for cancer and inflammatory diseases. University of Illinois Urbana-Champaign. July 01, 2024. Excerpt: Inflammatory cell death, necroptosis, is an important regulatory tool in the body’s arsenal against disease. In some diseases, the process is erratic; for example, cancer cells are able to suppress inflammatory signals and escape death. Note: “Usually treatments for cancer involve pharmacological induction to kill cells, however, the chemicals tend to diffuse throughout tissues and it’s hard to contain to a precise location. You get a lot of unwanted effects,” said study leader Kai Zhang, a professor of biochemistry. “We can make cells responsive to light, and we can focus the light beam to be smaller than one cell. That is how we can use light to precisely target a cell and turn on its death pathway.” Researchers use a method optogenetics to make cells respond to light. A light-activated gene from plants was inserted into intestinal cell culture, attaching it to the gene for RIPK3, a protein that regulates necroptosis. “When activated, RIPK3 undergoes oligomerization — forms clusters of protein complexes. Our light-sensitive proteins cluster together when exposed to blue light. By triggering light-sensitive proteins to come together, RIPK3 comes together and oligomerizes, and that’s how we mimic the activation pathway,” said graduate student Teak-Jung Oh, first author of the paper published in the Journal of Molecular Biology. Killing the cell is not the only goal. Inducing inflammatory cell death pathway, rather than outright killing the cell mechanically or chemically, triggers the immune system to respond. The ruptured cells release chemicals, cytokines that irritate nearby cells and attract T cells, white blood cells that play an important role in how the immune system identifies and attacks threats, Zhang said. “Certain cancer cell types create a local immunosuppressive environment, where T cells are either not recruited or, do not recognize it as a threat and do not infiltrate the cancerous area. By opening up some cancer cells through necroptosis, we hope to modulate the immune suppressive environment and help train T cells to recognize and attack the cancer,” said Zhang, a member of the Cancer Center at Illinois. Optogenetics requires light delivery directly to tissues, human clinical applications in tissues deeper than skin are currently limited. The Illinois group plans to implement their system in mice next to further study necroptosis and immune response in cancer and other inflammatory diseases. They also will further investigate the in vitro platform’s potential for training T cells for immune therapies. Link to published research enclosed. https://lnkd.in/ecBBeZ54

Neutrophils, the 'first responders' of our immune system, are far more complex than previously understood. Recent research, including a comprehensive review in Signal Transduction and Targeted Therapy, sheds light on their versatile roles, not just in fighting infections but also in contributing to various diseases. Traditionally, neutrophils were seen as simple soldiers, rapidly deploying to combat invading pathogens. However, new insights reveal their profound impact on both human health and disease. While they are crucial for eliminating bacteria and fungi through mechanisms like phagocytosis, degranulation, and the formation of Neutrophil Extracellular Traps (NETs), their dysregulation can lead to significant pathology. In infectious diseases, for instance, an overzealous neutrophil response can exacerbate conditions like sepsis, leading to organ damage. Conversely, certain pathogens have evolved to evade neutrophil defenses, highlighting the intricate dance between host and microbe. Beyond infections, neutrophils play a significant role in inflammatory disorders like rheumatoid arthritis and inflammatory bowel disease, and even in the complex landscape of cancer, where they can either suppress or promote tumor growth depending on the context. This evolving understanding of neutrophil diversity and function opens new avenues for therapeutic strategies. By targeting and modulating neutrophil activity, we could potentially develop more effective treatments for a wide range of conditions, from severe infections to chronic inflammatory diseases and cancer. What are your thoughts on the multifaceted roles of neutrophils? How do you think this deeper understanding will impact future medical interventions? #Neutrophils #Immunology #InfectiousDisease #Inflammation #CancerResearch #MedicalScience #Research #Health #Science Zhang, F., Xia, Y., Su, J. et al. Neutrophil diversity and function in health and disease. Sig Transduct Target Ther 9, 343 (2024). https://lnkd.in/gSKrwfR5