Only the abstract is available publicly. Toll-like receptors, particularly TLR-4 has been shown to be associated with insulin resistance. These TLRs have specific pathogen recognition sites. TLRs are stimulated by fatty acids (FA) and endotoxemia from bacteria. Thus, dietary intake of high trans fats, inflammation originating from the gut can be the source of insulin receptor dysfunction through TLRs.
Activation of the innate immune system controls macronutrient metabolism
the innate immune response is the first line of defense against invading pathogens, wherein highly conserved pathogen-associated molecular patterns (PAMPs) are recognized by cognate pattern recognition receptors (PRRs
many studies have supported the idea that cytokine signaling directly promotes insulin resistance
innate immune system may be causally linked to obesity
adipose tissue contains a substantial population of macrophages, and macrophage-driven adipose inflammation contributes significantly to the pathogenesis of obesity
Collectively, activation of the innate immune system is strongly associated with ASCVD, insulin resistance, and obesity, and recent evidence suggests that much of this association can be traced to a unique family of PRRs known as TLRs
TLRs are a family of type I transmembrane receptors, currently thought to comprise at least 13 members in mammals, that specifically recognize a variety of microbial PAMPs and trigger host cellular responses
Free SFAs have indeed been demonstrated to elicit TLR4-dependent and TLR2-dependent responses in several cell types.
Endogenous SFAs released from adipocytes activate cocultured macrophages via TLR4 [18], indicating the potential for cellular crosstalk in adipose tissue. Collectively, there is a growing body of evidence that SFAs promote, whereas long chain PUFA antagonize, TLR4-dependent and TLR2-dependent signaling in multiple cell models
In an elegant study, Shi et al. [16] demonstrated that SFAs activate TLR4-dependent signaling in both macrophages and adipocytes, and mice lacking TLR4 are protected against insulin resistance driven by intravenous lipid infusion
In addition to effects in macrophages and adipocytes, SFAs can activate TLR4 in the hypothalamus, which triggers a central inflammatory response that results in resistance to anorexigenic signals
endogenous SFAs can indeed promote innate immunity and inflammatory disease
This finding strongly supports the work of Hwang and coworkers [19–22] demonstrating that ω-3 PUFAs can effectively counteract SFA-induced TLR4 activation in cultured macrophages and dendritic cells.
high saturated fat intake (excess FFA) shown to contribute to obesity through TLR4 receptors. TLR4 receptors are mediators in the innate immunity. The result will be both IKK-Beta and NF-KappaB.
OMega-3 inhibits inflammation via decreased phosphorylation of lkappaBalpha and resultant decreased disassociation of NF-kappaB and decreased cytokine production. This occurs through TLR-4.
In addition to the antagonist effect on mu-opioid and other opioid receptors, naltrexone simultaneously has an antagonist effect on non-opioid receptors (Toll-like receptor 4 or TLR4) that are found on macrophages such as microglia
It is via the non-opioid antagonist path that LDN is thought to exert its anti-inflammatory effects
Once activated, microglia produce inflammatory and excitatory factors that can cause sickness behaviors such as pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise
The neuroprotective action appears to result when microglia activation in the brain and spinal cord is inhibited
By suppressing microglia activation, naloxone reduces the production of reactive oxygen species and other potentially neuroexcitatory and neurotoxic chemicals
suppressed TNF-alpha, IL-6, MCP-1, and other inflammatory agents in peripheral macrophages
individuals with greater ESR at baseline experienced a greater drop in pain when taking LDN
LDN has been reported to reduce not only self-reported pain in that condition but also objective markers of inflammation and disease severity
Naltrexone has also shown some promise in improving disease severity in multiple sclerosis
Stimulation of TLRs initiates intracellular signaling cascades resulting in downstream NF-B and mitogen-activated protein kinase activation and production of proinflammatory chemokines associated with mechanisms of metabolic dysfunction and cardiovascular disease progression.
Elevated fatty acids levels associated with obesity activate TLR4 signaling in fat cells and macrophages, and induce insulin resistance in murine models
Pneumonia is a typical symptom of COVID-19 infection, while acute respiratory distress syndrome (ARDS) and multiple organ failure are common in severe COVID-19 patients
Another indirect route of SARS-CoV-2-induced NET production is platelet activation
SARS-CoV-2 infection has also been linked to increased neutrophil-to-lymphocyte ratios, which is associated with disease severity and clinical prognosis
NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)
increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis
NETs are important for preventing pathogen invasion, their excessive formation can result in a slew of negative consequences, such as autoimmune inflammation and tissue damage
When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis
In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.
SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors
Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause
NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.
SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation
Connects SARS-CoV-2 to TLR on Platelets to NETosis to metastasis.
NET formation may be caused by activated platelets rather than SARS-CoV-2 itself
NETosis and NETs are increasingly recognized as causes of vascular injury
early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses
NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease
NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation
“cytokine storm”
SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19
NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response
patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]
can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes
have weakened adaptive immunity as well as a high level of inflammation
tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised
NETs have also been shown to enhance macrophage pyroptosis in sepsis
facilitating an immunosuppressive microenvironment
persistent immunosuppression may result in bacterial co-infection or secondary infection
COVID-19 NETs may act as potential inducers for autoimmune responses
NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection
Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness
NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells
COVID-19 also has a long-term influence on tumor progression
Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19
patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis
awaken cancer cells
NETs have been shown to change the tumor microenvironment
enhance tumor progression and metastasis
vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response
vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS
vitamin C may also inhibit NETosis and NET production in COVID-19
A subsequent study by Yuan et al. showed that Tnf treatment of 3T3L1 adipocytes induces insulin resistance and that this could be prevented by pretreatment of cells with aspirin
Activation of the Tnf receptor results in stimulation of NFκB signaling via Ikkb
the percentage of macrophages in a given adipose tissue depot is positively correlated with adiposity and adipocyte size
Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes
Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NFκB activation by reducing IKK activity [38]
adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression
One theory holds that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia and that large adipocytes outstrip the local oxygen supply leading to cell autonomous hypoxia with activation of cellular stress pathways
The use of the anti-inflammatory compounds, salicylate and its derivative aspirin, for treating symptoms of T2DM dates back over 100 years
elevated levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states
overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses
Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity
In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter
macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the “classically activated” pro-inflammatory macrophage, to the M2 state or the “alternatively activated” non-inflammatory cell
saturated fatty acids are the most potent inducers of this inflammatory response
Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes iNOS (reviewed in [33]
Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production
elevated JNK activity in liver, adipose tissue and skeletal muscle of obese insulin resistant mice, and knockout of Jnk1 (Jnk1−/−) leads to amelioration of insulin resistance in high fat diet
Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance
C-reactive protein (CRP)
these studies highlight the possibility that increased iNOS activity plays a direct role in the pathogenesis of insulin resistance
the important role of Ikkb in the development of obesity and inflammation-induced insulin resistance.
It is probable that local concentrations of inflammatory mediators, such as FFAs, Tnf or other cytokines/adipokines contribute to this polarity switch
Tnf and other cytokines/chemokines are symptomatic of inflammation, and while they propagate and/or maintain the inflammatory state, they are not the initial cause(s) of inflammation
Tlr4, in particular, is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria
Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system.
Tlr4 stimulation results in the activation of both Ikkb/NFκB and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1, etc. (reviewed in [57