Objective
Rheumatoid arthritis (RA) is considered to be a prototypical autoimmune disorder. Several mechanisms have been proposed for the known pathologic function of B cells in RA, including antigen ...presentation, cytokine secretion, and humoral immunity. The aim of this study was to address the function of B lymphocytes in experimental arthritis.
Methods
We mapped the adaptive immune response following collagen‐induced arthritis (CIA). We subsequently monitored these responses and disease outcomes in genetically modified mouse strains that lack mature B cell or germinal center (GC) functionality in a B cell–intrinsic manner.
Results
Following primary immunization, the draining lymph nodes broadly reacted against type II collagen (CII) with the formation of GCs and T cell activation. Mice that lacked mature B cell function were fully protected against CIA and had a severely attenuated ability to mount isotype‐switched humoral immune responses against CII. Almost identical results were observed in mice that were selectively deficient in GC responses. Importantly, GC‐deficient mice were fully susceptible to collagen antibody–induced arthritis.
Conclusion
We identified GC formation and anticollagen antibody production as the key pathogenic functions of B cells in CIA. The role of B cells in RA is likely to be more complex. However, targeting the GC reaction could allow for therapeutic interventions that are more refined than general B cell depletion.
Smoking is one of the most prominent addictions of the modern world, and one of the leading preventable causes of death worldwide. Although the number of tobacco smokers is believed to be at a ...historic low, electronic cigarette use has been on a dramatic rise over the past decades. Used as a replacement for cigarette smoking, electronic cigarettes were thought to reduce the negative effects of burning tobacco. Nonetheless, the delivery of nicotine by electronic cigarettes, the most prominent component of cigarette smoke (CS) is still delivering the same negative outcomes, albeit to a lesser extent than CS. Smoking has been shown to affect both the structural and functional aspects of major organs, including the lungs and vasculature. Although the deleterious effects of smoking on these organs individually is well-known, it is likely that the adverse effects of smoking on these organs will have long-lasting effects on the cardiovascular system. In addition, smoking has been shown to play an independent role in the homeostasis of the immune system, leading to major sequela. Both the adaptive and the innate immune system have been explored regarding CS and have been demonstrated to be altered in a way that promotes inflammatory signals, leading to an increase in autoimmune diseases, inflammatory diseases, and cancer. Although the mechanism of action of CS has not been fully understood, disease pathways have been explored in both branches of the immune system. The pathophysiologically altered immune system during smoking and its correlation with cardiovascular diseases is not fully understood. Here we highlight some of the important pathological mechanisms that involve cigarette smoking and its many components on cardiovascular disease and the immune systems in order to have a better understanding of the mechanisms at play.
The body's inflammatory response involves a series of processes that are necessary for the immune system to mitigate threats from invading pathogens. Leukocyte migration is a crucial process in both ...homeostatic and inflammatory states. The mechanisms involved in immune cell recruitment to the site of inflammation are numerous and require several cascades and cues of activation. Immune cells have multiple origins and can be recruited from primary and secondary lymphoid, as well as reservoir organs within the body to generate an immune response to certain stimuli. However, no matter the origin, an important aspect of any inflammatory response is the web of networks that facilitates immune cell trafficking. The vasculature is an important organ for this trafficking, especially during an inflammatory response, mainly because it allows cells to migrate towards the source of insult/injury and serves as a reservoir for leukocytes and granulocytes under steady state conditions. One of the most active and vital leukocytes in the immune system's arsenal are neutrophils. Neutrophils exist under two forms in the vasculature: a marginated pool that is attached to the vessel walls, and a demarginated pool that freely circulates within the blood stream. In this review, we seek to present the current consensus on the mechanisms involved in leukocyte margination and demargination, with a focus on the role of neutrophil migration patterns during physio-pathological conditions, in particular diabetes and cardiovascular disease.
Of all the different risk factors known to cause cardiovascular disease (CVD), age and sex are considered to play a crucial role. Aging follows a continuum from birth to death, and therefore it ...inevitably acts as a risk for CVD. Along with age, sex differences have also been shown to demonstrate variations in immune system responses to pathological insults. It has been widely perceived that females are protected against myocardial infarction (MI) and the protection is quite apparent in young vs. old women. Acute MI leads to changes in the population of myeloid and lymphoid cells at the injury site with myeloid bias being observed in the initial inflammation and the lymphoid in the late-resolution phases of the pathology. Multiple evidence demonstrates that aging enhances damage to various cellular processes through inflamm-aging, an inflammatory process identified to increase pro-inflammatory markers in circulation and tissues. Following MI, marked changes were observed in different sub-sets of major myeloid cell types viz., neutrophils, monocytes, and macrophages. There is a paucity of information regarding the tissue and site-specific functions of these sub-sets. In this review, we highlight the importance of age and sex as crucial risk factors by discussing their role during MI-induced myelopoiesis while emphasizing the current status of myeloid cell sub-sets. We further put forth the need for designing and executing age and sex interaction studies aimed to determine the appropriate age and sex to develop personalized therapeutic strategies post-MI.
•Age and sex represent the most important risk factors for heart disease.•Along with aging associated ‘inflamm-aging’, sex differences also show variations in response to pathological insults.•Acute inflammation driven by myelopoiesis is enhanced after acute MI, with a bias towards inflammatory monocytes formation.•There lies paucity in literature on tissue and site-specific functions driven by myelopoiesis after acute MI.•Clonal hematopoiesis, mosaic loss of Y chromosome and menopause are some of the key determinants in MI disease pathology.•The current state of understanding on age and sex interactions in MI induced myelopoiesis is inconclusive.•Experiments focused on such interactions are key for developing personalized therapeutic strategies post-MI in future.
Abstract
Neutrophils, the most abundant of all leucocytes and the first cells to arrive at the sites of sterile inflammation/injury act as a double-edged sword. On one hand, they inflict a ...significant collateral damage to the tissues and on the other hand, they help facilitate wound healing by a number of mechanisms. Recent studies have drastically changed the perception of neutrophils from being simple one-dimensional cells with an unrestrained mode of action to a cell type that display maturity and complex behaviour. It is now recognized that neutrophils are transcriptionally active and respond to plethora of signals by deploying a wide variety of cargo to influence the activity of other cells in the vicinity. Neutrophils can regulate macrophage behaviour, display innate immune memory, and play a major role in the resolution of inflammation in a context-dependent manner. In this review, we provide an update on the factors that regulate neutrophil production and the emerging dichotomous role of neutrophils in the context of cardiovascular diseases, particularly in atherosclerosis and the ensuing complications, myocardial infarction, and heart failure. Deciphering the complex behaviour of neutrophils during inflammation and resolution may provide novel insights and in turn facilitate the development of potential therapeutic strategies to manage cardiovascular disease.
Acute myocardial infarction (MI) results in overzealous production and infiltration of neutrophils to the ischemic heart. This is mediated in part by granulopoiesis induced by the ...S100A8/A9-NLRP3-IL-1β signaling axis in injury-exposed neutrophils. Despite the transcriptional upregulation of the NLRP3 (Nod Like Receptor Family Pyrin Domain-Containing 3) inflammasome and associated signaling components in neutrophils, the serum levels of IL-1β (interleukin-1β), the effector molecule in granulopoiesis, were not affected by MI, suggesting that IL-1β is not released systemically. We hypothesize that IL-1β is released locally within the bone marrow (BM) by inflammasome-primed and reverse-migrating neutrophils.
Using a combination of time-dependent parabiosis and flow cytometry techniques, we first characterized the migration patterns of different blood cell types across the parabiotic barrier. We next induced MI in parabiotic mice by permanent ligation of the left anterior descending artery and examined the ability of injury-exposed neutrophils to permeate the parabiotic barrier and induce granulopoiesis in noninfarcted parabionts. Last, using multiple neutrophil adoptive and BM transplant studies, we studied the molecular mechanisms that govern reverse migration and retention of the primed neutrophils, IL-1β secretion, and granulopoiesis. Cardiac function was assessed by echocardiography.
MI promoted greater accumulation of the inflammasome-primed neutrophils in the BM. Introducing a time-dependent parabiotic barrier to the free movement of neutrophils inhibited their ability to stimulate granulopoiesis in the noninfarcted parabionts. Previous priming of the NLRP3 inflammasome is not a prerequisite, but the presence of a functional CXCR4 (C-X-C-motif chemokine receptor 4) on the primed-neutrophils and elevated serum S100A8/A9 levels are necessary for homing and retention of the reverse-migrating neutrophils. In the BM, the primed-neutrophils secrete IL-1β through formation of gasdermin D pores and promote granulopoiesis. Pharmacological and genetic strategies aimed at the inhibition of neutrophil homing or release of IL-1β in the BM markedly suppressed MI-induced granulopoiesis and improved cardiac function.
Our data reveal a new paradigm of how circulatory cells establish a direct communication between organs by delivering signaling molecules (eg, IL-1β) directly at the sites of action rather through systemic release. We suggest that this pathway may exist to limit the off-target effects of systemic IL-1β release.
Neutrophil behavior and function are altered by hyperglycemia associated with diabetes. Aberrant activation by hyperglycemia causes neutrophils to respond with increased production of reactive ...oxidative species (ROS). Excess ROS, a signature of primed neutrophils, can intracellularly induce neutrophils to undergo NETosis, flooding surrounding tissues with ROS and damage-associated molecular patterns such as S100 calcium binding proteins (S100A8/A9). The cargo associated with NETosis also attracts more immune cells to the site and signals for increased immune cell production. This inflammatory response to diabetes can accelerate other associated conditions such as atherosclerosis and thrombosis, increasing the risk of cardiovascular disease.
As the prevalence of diabetes continues to grow, more attention has been focused on developing effective treatment options. Currently, glucose-lowering medications and insulin injections are the most widely utilized treatments. As the disease progresses, medications are usually stacked to maintain glucose at desired target levels, but this approach often fails and does not effectively reduce cardiovascular risk, even with the latest drugs.
Despite advances in treatment options, diabetes remains a progressive disease as glucose lowering alone has failed to abolish the associated cardiovascular complications.
Significant interest is being generated in developing treatments that do not solely focus on glucose control but rather mitigate glucotoxicity. Several therapies have been proposed that target cellular dysfunction downstream of hyperglycemia, such as using antioxidants to scavenge ROS, inhibiting ROS production from NOX, and suppressing neutrophil release of S100A8/A9 proteins.
. 36, 652-666.
Pain is one of the first presenting symptoms in patients with head and neck cancer, who often develop chronic and debilitating pain as the disease progresses. Pain is also an important prognostic ...marker for survival. Unfortunately, patients rarely receive effective pain treatment due to our limited knowledge of the mechanisms underlying head and neck cancer pain (HNCP). Pain is often associated with neuroinflammation and particularly interleukin (IL)-1 signaling. The purpose of this study is to develop a novel syngeneic model of HNCP in immunocompetent mice to examine the contribution of IL-1 signaling.
Male C57BL/6 mice were injected with a murine model of human papillomavirus (HPV+)-induced oropharyngeal squamous cell carcinoma in their right hindlimb to induce tumor growth. Pain sensitivity was measured via von Frey filaments. Spontaneous pain was assessed via the facial grimace scale. IL-1β was measured by quantifying gene expression via quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA).
Pain hypersensitivity and spontaneous pain develop quickly after the implantation of tumor cells, a time when tumor volume is still insignificant. Spinal and circulating IL-1β levels are significantly elevated in tumor-bearing mice. Blocking IL-1 signaling either by intrathecal administration of interleukin-1 receptor antagonist (IL-1ra) or by genetic deletion (interleukin-1 receptor knockout Il1r1-/-) does not alleviate HNCP.
We established the first syngeneic model of HNCP in immunocompetent mice. Unlike inflammatory or nerve-injured pain, HNCP is independent of IL-1 signaling. These findings challenge the common belief that pain results from tissue compression or IL-1 signaling in patients with head and neck cancer.
Controlling the overwhelming inflammatory reaction associated with polymicrobial sepsis remains a prevalent clinical challenge with few treatment options. In septic peritonitis, blood neutrophils and ...monocytes are rapidly recruited into the peritoneal cavity to control infection, but the role of resident sentinel cells during the early phase of infection is less clear. In particular, the influence of mast cells on other tissue-resident cells remains poorly understood. Here, we developed a mouse model that allows both visualization and conditional ablation of mast cells and basophils to investigate the role of mast cells in severe septic peritonitis. Specific depletion of mast cells led to increased survival rates in mice with acute sepsis. Furthermore, we determined that mast cells impair the phagocytic action of resident macrophages, thereby allowing local and systemic bacterial proliferation. Mast cells did not influence local recruitment of neutrophils and monocytes or the release of inflammatory cytokines. Phagocytosis inhibition by mast cells involved their ability to release prestored IL-4 within 15 minutes after bacterial encounter, and treatment with an IL-4-neutralizing antibody prevented this inhibitory effect and improved survival of septic mice. Our study uncovers a local crosstalk between mast cells and macrophages during the early phase of sepsis development that aggravates the outcome of severe bacterial infection.
Objective- Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic ...inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. Approach and Results- We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe
mice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Conclusions- Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis.
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