Chinese Researchers Uncover The Critical Role Of Adaptor Proteins In Sepsis Regulation

The Discovery: A New Hope for Sepsis Treatment
In a groundbreaking study, scientists from The Second Affiliated Hospital at Zhejiang University School of Medicine in Hangzhou, China, have uncovered the pivotal role that adaptor proteins play in regulating the innate immune response during sepsis. Sepsis, a life-threatening condition caused by an overwhelming immune response to infection, remains a significant health challenge worldwide, with high mortality rates and limited effective treatments. This new Sepsis Research offers promising insights that could lead to more targeted and effective therapies for this devastating condition.


Signaling pathways and key adaptor proteins in sepsis and novel methods for the treatment of sepsis by targeting adaptor proteins. Abbreviations: ALK, anaplastic lymphoma kinase; ASC, apoptosis-associated speck-like protein containing a caspase-recruitment domain; BCAP, B-cell adaptor for phosphoinositide 3-kinase; CD14, leukocyte differentiation antigen 14; CDNs, cyclic dinucleotides; cGAMP, cyclic guanosine monophosphate–adenosine monophosphate; cGAS, cyclic guanosine monophosphate–adenosine monophosphate synthase; EVS, extracellular vesicles; IFN, interferon; IL, interleukin; IKK, inhibitor of κB kinase; IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7; Keap1, Kelch-like ECH-associated protein 1; LBP, lipopolysaccharide-binding protein; LGP2, laboratory of genetics and physiology 2; LPS, lipopolysaccharide; MAL, MyD88 adaptor-like protein; MAPK, mitogen activated protein kinase; MAVS, mitochondrial antiviral signaling protein; MD-2, myeloid differentiation protein 2; MDA5, melanoma differentiation associated factor 5; MyD88, Myeloid differentiation primary response protein 88; NCOA4, nuclear receptor coactivator 4; NF-κB, nuclear factor kappa-B; NLRP3, NOD-like receptor thermal protein domain associated protein 3; Nrf2, nuclear factor erythroid-2 related factor-2; RIG-I, retinoic acid-inducible gene; ROS, reactive oxygen species; SIGIRR, single immunoglobulin IL-1R-related receptor; STING, stimulator of interferon genes; TLR1-9, Toll like receptor1-9.

Sepsis: A Global Health Challenge
Sepsis is a severe systemic inflammatory response syndrome that leads to multiple organ dysfunction. It occurs when the body's immune response to infection becomes dysregulated. This condition affects millions of people globally, with mortality rates ranging from 20% to 30% depending on the region. Despite advances in medical care, including improved diagnosis and management strategies, sepsis continues to be a major health concern due to the lack of specific and effective treatments.
 
The Role of the Innate Immune System in Sepsis
The human immune system comprises two main components: the innate and adaptive immune systems. The innate immune system acts as the first line of defense against pathogens, providing a rapid but non-specific response to infections. In sepsis, the innate immune system often becomes hyperactive, leading to excessive inflammation. This overreaction res ults in the production of numerous pro-inflammatory cytokines and inflammasomes, which can cause oxidative stress and various forms of regulated cell death, including pyroptosis, apoptosis, and ferroptosis.
 
Adaptor Proteins: The Key Players
Adaptor proteins are crucial in facilitating protein-protein interactions within various signaling pathways, especially during the immune response in sepsis. These proteins, which lack catalytic or transcriptional activity, recruit functional proteins to form multiprotein signaling complexes, playing significant roles in signal transduction. The research highlights several key adaptor proteins involved in sepsis-related signaling pathways:
 
-MyD88: A central adaptor protein in the Toll-like receptor (TLR) signaling pathway, MyD88 is essential for recruiting proteins that activate inflammatory responses. Its role in sepsis is well-documented, with studies showing that inhibiting MyD88 can reduce inflammation and improve outcomes in septic models.
 
-TRIF: Another important adaptor protein in the TLR signaling pathway, TRIF mediates MyD88-independent signaling. Research indicates that TRIF is crucial for inducing type I interferons and activating NF-κB, both of which play roles in the immune response to sepsis.
 
-MAVS: In the retinoic acid-inducible gene I-like receptor (RLR) pathway, MAVS is pivotal for antiviral responses. The study found that MAVS is involved in sepsis triggered by viral infections, with its activation leading to the production of interferons and inflammatory cytokines.
 
-STING: The stimulator of interferon genes (STING) pathway is crucial for detecting cytosolic DNA and activating innate immune responses. The research highlights STING's role in mediating inflammation and coagulation in sepsis, making it a potential therapeutic target.
 
-NLRP3: The NLRP3 inflammasome is a sensor of cellular stress and plays a significant role in the inflammatory response during sepsis. Inhibiting NLRP3 can reduce inflammation and improve survival in septic models, making it a promising target for therapy.
 
Therapeutic Potential: Targeting Adaptor Proteins
The study explores the therapeutic potential of targeting adaptor proteins in sepsis treatment. By modulating these proteins, it may be possible to correct the dysregulated immune response and reduce the harmful effects of excessive inflammation. Several strategies are discussed:
 
TLR Pathway Inhibitors
-MD-2 Antagonists: MD-2 is a critical adaptor in the TLR4 signaling pathway, recognizing lipopolysaccharides (LPS) from bacterial cell walls. Compounds like eritoran, which competes with LPS for binding to MD-2, have shown promise in reducing mortality in septic models. However, clinical trials have yet to demonstrate significant benefits, highlighting the need for further research.
 
-MyD88 Inhibitors: Small molecules that disrupt the interaction between MyD88 and its associated receptors have been developed. These inhibitors can block the downstream signaling pathways that lead to inflammation, offering a potential therapeutic approach.
 
MAVS and STING Pathway Inhibitors
-Lactate Inhibition: Lactate has been identified as a natural inhibitor of MAVS, a key protein in the antiviral response during sepsis. Reducing lactate levels through compounds like sodium oxamate can enhance the immune response and protect against viral sepsis.
 
-STING Inhibitors: Various small molecules, including nitro-fatty acids and nitrofurans, have been found to inhibit STING signaling. These inhibitors can reduce the inflammatory response and have shown potential in preclinical models of sepsis.
 
NLRP3 Inflammasome Inhibitors
-MCC950: This small molecule inhibits the NLRP3 inflammasome and has shown efficacy in reducing inflammation in septic models. However, its clinical development has been hampered by concerns over hepatotoxicity.
 
-Lonidamine (LND): Targeting ASC, an adaptor protein in the NLRP3 inflammasome, LND has shown anti-inflammatory effects and may offer a new therapeutic avenue for sepsis treatment.
 
Keap1/Nrf2 Pathway Modulation
-Nrf2 Activation: Enhancing the Nrf2 pathway, which regulates antioxidant responses, can protect against oxidative stress-induced damage in sepsis. Compounds that disrupt the Keap1-Nrf2 interaction, such as pyrroloquinoline quinone (PQQ) and GYY4137, have demonstrated protective effects in septic models.
 
Conclusion: A Promising Future
The discovery of the crucial role of adaptor proteins in regulating the innate immune response during sepsis opens up new avenues for treatment. Targeting these proteins offer the potential to modulate the immune response, reduce excessive inflammation, and improve outcomes for patients with sepsis. While the path to clinical application is long and fraught with challenges, the promising findings from this research provide hope for more effective and targeted therapies in the future. As the understanding of adaptor proteins and their roles in sepsis deepens, the development of new drugs and therapeutic strategies will continue to evolve, potentially transforming the management and prognosis of this life-threatening condition.
 
The study findings were published in the peer reviewed journal: Pharmacological Research
https://www.sciencedirect.com/science/article/pii/S1043661824001671
 
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