scholarly journals Innate Immune Signaling and Its Role in Metabolic and Cardiovascular Diseases

2019 ◽  
Vol 99 (1) ◽  
pp. 893-948 ◽  
Author(s):  
Meng Xu ◽  
Peter P. Liu ◽  
Hongliang Li
Keyword(s):  
Transcription Factors ◽  
Immune System ◽  
Innate Immune System ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Immune Signaling ◽  
Cardiometabolic Diseases ◽  
Innate Immune Signaling ◽  
Cardiometabolic Disorders ◽  
Signaling Components

The innate immune system is an evolutionarily conserved system that senses and defends against infection and irritation. Innate immune signaling is a complex cascade that quickly recognizes infectious threats through multiple germline-encoded cell surface or cytoplasmic receptors and transmits signals for the deployment of proper countermeasures through adaptors, kinases, and transcription factors, resulting in the production of cytokines. As the first response of the innate immune system to pathogenic signals, inflammatory responses must be rapid and specific to establish a physical barrier against the spread of infection and must subsequently be terminated once the pathogens have been cleared. Long-lasting and low-grade chronic inflammation is a distinguishing feature of type 2 diabetes and cardiovascular diseases, which are currently major public health problems. Cardiometabolic stress-induced inflammatory responses activate innate immune signaling, which directly contributes to the development of cardiometabolic diseases. Additionally, although the innate immune elements are highly conserved in higher-order jawed vertebrates, lower-grade jawless vertebrates lack several transcription factors and inflammatory cytokine genes downstream of the Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) pathways, suggesting that innate immune signaling components may additionally function in an immune-independent way. Notably, recent studies from our group and others have revealed that innate immune signaling can function as a vital regulator of cardiometabolic homeostasis independent of its immune function. Therefore, further investigation of innate immune signaling in cardiometabolic systems may facilitate the discovery of new strategies to manage the initiation and progression of cardiometabolic disorders, leading to better treatments for these diseases. In this review, we summarize the current progress in innate immune signaling studies and the regulatory function of innate immunity in cardiometabolic diseases. Notably, we highlight the immune-independent effects of innate immune signaling components on the development of cardiometabolic disorders.

scholarly journals Emerging Roles of Protein Deamidation in Innate Immune Signaling

2016 ◽  
Vol 90 (9) ◽  
pp. 4262-4268 ◽  
Author(s):  
Jun Zhao ◽  
Junhua Li ◽  
Simin Xu ◽  
Pinghui Feng
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Biological Processes ◽  
Innate Immune Responses ◽  
Immune Signaling ◽  
Host Immune Responses ◽  
Innate Immune Signaling ◽  
Enzyme Deficient ◽  
Signaling Components

Protein deamidation has been considered a nonenzymatic process associated with protein functional decay or “aging.” Recent studies implicate protein deamidation in regulating signal transduction in fundamental biological processes, such as innate immune responses. Work investigating gammaherpesviruses and bacterial pathogens indicates that microbial pathogens deploy deamidases or enzyme-deficient homologues (pseudoenzymes) to induce deamidation of key signaling components and evade host immune responses. Here, we review studies on protein deamidation in innate immune signaling and present several imminent questions concerning the roles of protein deamidation in infection and immunity.

scholarly journals Effect of Hypoglycemia on Inflammatory Responses and the Response to Low-Dose Endotoxemia in Humans

2018 ◽  
Vol 104 (4) ◽  
pp. 1187-1199 ◽  
Author(s):  
Ahmed Iqbal ◽  
Lynne R Prince ◽  
Peter Novodvorsky ◽  
Alan Bernjak ◽  
Mark R Thomas ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Immune System ◽  
Innate Immune System ◽  
Low Dose ◽  
Inflammatory Responses ◽  
Platelet Reactivity ◽  
Innate Immune ◽  
Endotoxin Challenge ◽  
Intermediate Monocytes

Abstract Context Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting Single-blinded, prospective study of three independent parallel groups. Participants and Interventions Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main Outcome Measures We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P < 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/μL vs euglycemia 20.66 ± 3.43/μL, P < 0.01; vs sham-saline 26.20 ± 3.86/μL, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/μL vs euglycemia 12.72 ± 2.42/μL, P < 0.001; vs sham-saline 19.05 ± 3.81/μL, P < 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P < 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/μL vs 49.32 ± 6.41/μL, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/μL vs euglycemia 4.19 ± 1.08/μL, P < 0.05; vs sham-saline 3.81± 1.42/μL, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/μL vs euglycemia 2.86 ± 0.72/μL, P < 0.01; vs sham-saline 3.08 ± 1.01/μL, P < 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P < 0.05). Conclusions Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.

scholarly journals Bcr and Abr Cooperate in Negatively Regulating Acute Inflammatory Responses

2009 ◽  
Vol 29 (21) ◽  
pp. 5742-5750 ◽  
Author(s):  
Jess M. Cunnick ◽  
Sabine Schmidhuber ◽  
Gang Chen ◽  
Min Yu ◽  
Sun-Ju Yi ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Inflammatory Responses ◽  
Small Gtpase ◽  
Innate Immune ◽  
Ros Production ◽  
Activated Neutrophils ◽  
Inflammatory Processes ◽  
Null Mutant Mice

ABSTRACT Bcr and Abr are GTPase-activating proteins for the small GTPase Rac. Both proteins are expressed in cells of the innate immune system, including neutrophils and macrophages. The function of Bcr has been linked to the negative regulation of neutrophil reactive oxygen species (ROS) production, but the function of Abr in the innate immune system was unknown. Here, we report that mice lacking both proteins are severely affected in two models of experimental endotoxemia, including exposure to Escherichia coli lipopolysaccharide and polymicrobial sepsis, with extensive microvascular leakage, resulting in severe pulmonary edema and hemorrhage. Additionally, in vivo-activated neutrophils of abr and bcr null mutant mice produced excessive tissue-damaging myeloperoxidase (MPO), elastase, and ROS. Moreover, the secretion of the tissue metalloproteinase MMP9 by monocytes and ROS by elicited macrophages was abnormally high. In comparison, ROS production from bone marrow monocytes was not significantly different from that of controls, and the exocytosis of neutrophil secondary and tertiary granule products, including lactoferrin, was normal. These data show that Abr and Bcr normally curb very specific functions of mature tissue innate immune cells, and that each protein has distinct as well as partly overlapping functions in the downregulation of inflammatory processes.

scholarly journals Interleukin-37 regulates innate immune signaling in human and mouse colonic organoids

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joannie M. Allaire ◽  
Anita Poon ◽  
Shauna M. Crowley ◽  
Xiao Han ◽  
Zohreh Sharafian ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Individual Variability ◽  
Innate Immune ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Immune Signaling ◽  
Strong Expression ◽  
Innate Immune Signaling ◽  
Close Proximity ◽  
Species Specific

AbstractIntestinal epithelial cells (IEC) reside in close proximity to the gut microbiota and are hypo-responsive to bacterial products, likely to prevent maladaptive inflammatory responses. This is in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. IL-37 is an anti-inflammatory cytokine that inhibits innate signaling in diverse cells by signaling through SIGIRR. Despite the strong expression of SIGIRR by IEC, few studies have examined whether IL-37 can suppress their innate immune signaling. We characterized innate immune responses of human and murine colonoids to bacteria (FliC, LPS) and host (IL-1β) products and the role of IL-37/SIGIRR in regulating these responses. We demonstrated that human colonoids responded only to FliC, but not to LPS or IL-1β. While colonoids derived from different donors displayed significant inter-individual variability in the magnitude of their innate responses to FliC stimulation, all colonoids released a variety of chemokines. Interestingly, IL-37 attenuated these responses through inhibition of p38 and NFκB signaling pathways. We determined that this suppression by IL-37 was SIGIRR dependent, in murine organoids. Along with species-specific differences in IEC innate responses, we show that IL-37 can promote IEC hypo-responsiveness by suppressing inflammatory signaling.

scholarly journals Interleukin-37 Regulates Innate Immune Signaling in Human and Mouse Colonic Organoids

2020 ◽  
Author(s):  
Joannie Allaire ◽  
Anita Poon ◽  
Shauna Crowley ◽  
Xiao Han ◽  
Navjit Moore ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Individual Variability ◽  
Innate Immune ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Immune Signaling ◽  
Strong Expression ◽  
Innate Immune Signaling ◽  
Close Proximity ◽  
Species Specific

Abstract Intestinal epithelial cells (IEC) reside in close proximity to the gut microbiota and are hypo-responsive to bacterial products, likely to prevent maladaptive inflammatory responses. This is in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. IL-37, an anti-inflammatory cytokine that inhibits innate signaling in diverse cells by signaling through SIGIRR. Despite the strong expression of SIGIRR by IEC, few studies have examined whether IL-37 can suppress their innate immune signaling. We characterized innate immune responses of human and murine colonoids to bacteria (FliC, LPS) and host (IL-1β) products and the role of IL-37/SIGIRR in regulating these responses. We demonstrated that human colonoids responded only to FliC, but not to LPS or IL-1β. While colonoids derived from different donors displayed significant inter-individual variability in the magnitude of their innate responses to FliC stimulation, all colonoids released a variety of chemokines. Interestingly, IL-37 attenuated these responses through inhibition of p38 and NFκB signaling pathways. We determined that this suppression by IL-37 was SIGIRR dependent, in murine organoids. Along with species-specific differences in IEC innate responses, we show that IL-37 can promote IEC hypo-responsiveness by supressing inflammatory signaling.

scholarly journals The Interactions between Nanoparticles and the Innate Immune System from a Nanotechnologist Perspective

Nanomaterials ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2991
Author(s):  
Lena M. Ernst ◽  
Eudald Casals ◽  
Paola Italiani ◽  
Diana Boraschi ◽  
Victor Puntes
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Inorganic Nanoparticles ◽  
Cellular Debris ◽  
Abnormal Cells ◽  
Nanoparticle Design ◽  
Modes Of Interaction ◽  
Molecular Patterns

The immune system contributes to maintaining the body’s functional integrity through its two main functions: recognizing and destroying foreign external agents (invading microorganisms) and identifying and eliminating senescent cells and damaged or abnormal endogenous entities (such as cellular debris or misfolded/degraded proteins). Accordingly, the immune system can detect molecular and cellular structures with a spatial resolution of a few nm, which allows for detecting molecular patterns expressed in a great variety of pathogens, including viral and bacterial proteins and bacterial nucleic acid sequences. Such patterns are also expressed in abnormal cells. In this context, it is expected that nanostructured materials in the size range of proteins, protein aggregates, and viruses with different molecular coatings can engage in a sophisticated interaction with the immune system. Nanoparticles can be recognized or passed undetected by the immune system. Once detected, they can be tolerated or induce defensive (inflammatory) or anti-inflammatory responses. This paper describes the different modes of interaction between nanoparticles, especially inorganic nanoparticles, and the immune system, especially the innate immune system. This perspective should help to propose a set of selection rules for nanosafety-by-design and medical nanoparticle design.

scholarly journals Critical Role for MyD88-Mediated Neutrophil Recruitment during Clostridium difficile Colitis

2012 ◽  
Vol 80 (9) ◽  
pp. 2989-2996 ◽  
Author(s):  
Irene Jarchum ◽  
Mingyu Liu ◽  
Chao Shi ◽  
Michele Equinda ◽  
Eric G. Pamer
Keyword(s):  
Clostridium Difficile ◽  
Inflammatory Responses ◽  
Adaptor Protein ◽  
Neutrophil Recruitment ◽  
Innate Immune ◽  
Antibiotic Administration ◽  
Immune Signaling ◽  
Content Type ◽  
Innate Immune Signaling ◽  
Deficient Mice

ABSTRACTClostridium difficilecan infect the large intestine and cause colitis when the normal intestinal microbiota is altered by antibiotic administration. Little is known about the innate immune signaling pathways that marshal inflammatory responses toC. difficileinfection and whether protective and pathogenic inflammatory responses can be dissociated. Toll-like receptors predominantly signal via the MyD88 adaptor protein and are important mediators of innate immune signaling in the intestinal mucosa. Here, we demonstrate that MyD88-mediated signals trigger neutrophil and CCR2-dependent Ly6Chimonocyte recruitment to the colonic lamina propria (cLP) during infection, which prevent dissemination of bystander bacteria to deeper tissues. Mortality is markedly increased in MyD88-deficient mice followingC. difficileinfection, as are parameters of mucosal tissue damage and inflammation. Antibody-mediated depletion of neutrophils markedly increases mortality, while attenuated recruitment of Ly6Chimonocytes in CCR2-deficient mice does not alter the course ofC. difficileinfection. Expression of CXCL1, a neutrophil-recruiting chemokine, is impaired in the cLP of MyD88−/−mice. Our studies suggest that MyD88-mediated signals promote neutrophil recruitment by inducing expression of CXCL1, thereby providing critical early defense againstC. difficile-mediated colitis.

The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

2017 ◽  
Vol 387 ◽  
pp. 46-60 ◽  
Author(s):  
Weijun Wang ◽  
Yaxing Zhang ◽  
Ling Yang ◽  
Hongliang Li
Keyword(s):  
Innate Immune ◽  
Immune Signaling ◽  
Cardiometabolic Diseases ◽  
Innate Immune Signaling

scholarly journals The Many Faces of Innate Immunity in SARS-CoV-2 Infection

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 596
Author(s):  
Nicholas Hanan ◽  
Ronnie L. Doud ◽  
In-Woo Park ◽  
Harlan P. Jones ◽  
Stephen O. Mathew
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
System A ◽  
Genetic Risks ◽  
Poor Outcomes ◽  
The Many ◽  
Lung Tissue Damage

The innate immune system is important for initial antiviral response. SARS-CoV-2 can result in overactivity or suppression of the innate immune system. A dysregulated immune response is associated with poor outcomes; with patients having significant Neutrophil-to-Lymphocyte ratios (NLR) due to neutrophilia alongside lymphopenia. Elevated interleukin (IL)-6 and IL-8 leads to overactivity and is a prominent feature of severe COVID-19 patients. IL-6 can result in lymphopenia; where COVID-19 patients typically have significantly altered lymphocyte subsets. IL-8 attracts neutrophils; which may play a significant role in lung tissue damage with the formation of neutrophil extracellular traps leading to cytokine storm or acute respiratory distress syndrome. Several factors like pre-existing co-morbidities, genetic risks, viral pathogenicity, and therapeutic efficacy act as important modifiers of SARS-CoV-2 risks for disease through an interplay with innate host inflammatory responses. In this review, we discuss the role of the innate immune system at play with other important modifiers in SARS-CoV-2 infection.

Sign in / Sign up

Export Citation Format

Share Document