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Selective neuron loss in discrete brain regions is a hallmark of various neurodegenerative disorders, although the mechanisms responsible for this regional vulnerability of neurons remain largely unknown. Earlier studies attributed neuron dysfunction and eventual loss during neurodegenerative diseases as exclusively cell autonomous. Although cell-intrinsic factors are one critical aspect in dictating neuron death, recent evidence also supports the involvement of other central nervous system cell types in propagating non-cell autonomous neuronal injury during neurodegenerative diseases. One such example is astrocytes, which support neuronal and synaptic function, but can also contribute to neuroinflammatory processes through robust chemokine secretion. Indeed, aberrations in astrocyte function have been shown to negatively impact neuronal integrity in several neurological diseases. The present review focuses on neuroinflammatory paradigms influenced by neuron-astrocyte cross-talk in the context of select neurodegenerative diseases.

Alzheimer's disease (AD) is a progressive disease that causes an impairment of learning and memory. Despite the highly complex pathogenesis of AD, amyloid beta (Aβ) deposition and neurofibrillary tangles (NFTs) formation are the main hallmarks of AD. Neuroinflammation also has a crucial role in the development of AD. As the central nervous system's innate immune cells, microglial cells are activated in AD and induce inflammation by producing pro‐inflammatory mediators. However, microglial activation is not always deleterious. M2‐activated microglial cells are considered anti‐inflammatory cells, which develop neuroprotection. Various approaches are proposed for managing AD, yet no effective therapy is available for this disorder. Considering the potential protective role of M2 microglia in neurodegenerative disorders and the improvement of these disorders by preconditioning approaches, it can be suggested that preconditioning of microglial cells may be beneficial for managing AD progression. Therefore, this study review microglial preconditioning approaches for preventing and improving AD. [ABSTRACT FROM AUTHOR]

Determining the precise course of bacterial infection requires abundant in vivo real‐time data. Synchronous monitoring of the bacterial load, temperature, and immune response can satisfy the shortage of real‐time in vivo data. Here, we conducted a study in the joint‐infected mouse model to synchronously monitor the bacterial load, temperature, and immune response using the second near‐infrared (NIR‐II) fluorescence imaging, infrared thermography, and immune response analysis for 2 weeks. Staphylococcus aureus (S. aureus) was proved successfully labeled with glucose‐conjugated quantum dots in vitro and in subcutaneous‐infected model. The bacterial load indicated by NIR‐II fluorescence imaging underwent a sharp drop at 1 day postinfection. At the same time, the temperature gap detected through infrared thermography synchronously brought by infection reached lowest value. Meanwhile, the flow cytometry analysis demonstrated that immune response including macrophage, neutrophil, B lymphocyte, and T lymphocyte increased to the peak at 1 day postinfection. Moreover, both M1 macrophage and M2 macrophage in the blood have an obvious change at ~ 1 day postinfection, and the change was opposite. In summary, this study not only obtained real‐time and long‐time in vivo data on the bacterial load, temperature gap, and immune response in the mice model of S. aureus infection, but also found that 1 day postinfection was the key time point during immune response against S. aureus infection. Our study will contribute to synchronously and precisely studying the complicated complex dynamic relationship after bacterial infection at the animal level. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major cause of morbidity and mortality globally. We unveiled the diagnostic value of serum NLRP3, metalloproteinase‐9 (MMP‐9) and interferon‐γ (IFN‐γ) levels in post‐craniotomy intracranial infections and hydrocephalus in patients with severe craniocerebral trauma to investigate the high risk factors for these in patients with TBI, and the serological factors predicting prognosis, which had a certain clinical predictive value. Study subjects underwent bone flap resection surgery and were categorized into the intracranial infection/hydrocephalus/control (without postoperative hydrocephalus or intracranial infection) groups, with their clinical data documented. Serum levels of NLRP3, MMP‐9 and IFN‐γ were determined using ELISA kits, with their diagnostic efficacy on intracranial infections and hydrocephalus evaluated by receiver operating characteristic curve analysis. The independent risk factors affecting postoperative intracranial infections and hydrocephalus were analysed by logistic multifactorial regression. The remission after postoperative symptomatic treatment was counted. The intracranial infection/control groups had significant differences in Glasgow Coma Scale (GCS) scores, opened injury, surgical time and cerebrospinal fluid leakage, whereas the hydrocephalus and control groups had marked differences in GCS scores, cerebrospinal fluid leakage and subdural effusion. Serum NLRP3, MMP‐9 and IFN‐γ levels were elevated in patients with post‐craniotomy intracranial infections/hydrocephalus. The area under the curve values of independent serum NLRP3, MMP‐9, IFN‐γ and their combination for diagnosing postoperative intracranial infection were 0.822, 0.722, 0.734 and 0.925, respectively, and for diagnosing hydrocephalus were 0.865, 0.828, 0.782 and 0.957, respectively. Serum NLRP3, MMP‐9 and IFN‐γ levels and serum NLRP3 and MMP‐9 levels were independent risk factors influencing postoperative intracranial infection and postoperative hydrocephalus, respectively. Patients with hydrocephalus had a high remission rate after postoperative symptomatic treatment. Serum NLRP3, MMP‐9 and IFN‐γ levels had high diagnostic efficacy in patients with postoperative intracranial infection and hydrocephalus, among which serum NLRP3 level played a major role. What is the central question of this study?Severe craniocerebral injury usually leads to the loss of nerve function: what is the diagnostic value of serum NLRP3, metalloproteinase‐9 (MMP‐9) and interferon‐γ (IFN‐γ) levels in the diagnosis of intracranial infections and hydrocephalus in patients with severe craniocerebral trauma after craniotomy?What is the main finding and its importance?Serum NLRP3, MMP‐9, and IFN‐γ levels had high diagnostic efficacy in patients with postoperative intracranial infection and hydrocephalus, among which serum NLRP3 level played a major role. [ABSTRACT FROM AUTHOR]

Since cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway was discovered in 2013, great progress has been made to elucidate the origin, function, and regulating mechanism of cGAS–STING signaling pathway in the past decade. Meanwhile, the triggering and transduction mechanisms have been continuously illuminated. cGAS–STING plays a key role in human diseases, particularly DNA‐triggered inflammatory diseases, making it a potentially effective therapeutic target for inflammation‐related diseases. Here, we aim to summarize the ancient origin of the cGAS–STING defense mechanism, as well as the triggers, transduction, and regulating mechanisms of the cGAS–STING. We will also focus on the important roles of cGAS–STING signal under pathological conditions, such as infections, cancers, autoimmune diseases, neurological diseases, and visceral inflammations, and review the progress in drug development targeting cGAS–STING signaling pathway. The main directions and potential obstacles in the regulating mechanism research and therapeutic drug development of the cGAS–STING signaling pathway for inflammatory diseases and cancers will be discussed. These research advancements expand our understanding of cGAS–STING, provide a theoretical basis for further exploration of the roles of cGAS–STING in diseases, and open up new strategies for targeting cGAS–STING as a promising therapeutic intervention in multiple diseases. [ABSTRACT FROM AUTHOR]

Citrobacter braakii (C. braakii) is an anaerobic, gram‐negative bacterium that has been isolated from the environment, food, and humans. Infection by C. braakii has been associated with acute mucosal inflammation in the intestine, respiratory tract, and urinary tract. However, the pathogenesis of C. braakii in the gastric mucosa has not yet been clarified. In this study, the bacterium was detected in 35.5% (61/172) of patients with chronic gastritis (CG) and was closely associated with the severity of mucosal inflammation. Citrobacter braakii P1 isolated from a patient with CG exhibited urease activity and acid resistance. It contained multiple secretion systems, including a complete type I secretion system (T1SS), T5aSS and T6SS. We then predicted the potential pilus‐related adhesins. Citrobacter braakii P1 diffusely adhered to AGS cells and significantly increased lactate dehydrogenase (LDH) release; the adhesion rate and LDH release were much lower in HEp‐2 cells. Strain P1 also induced markedly increased mRNA and protein expression of IL‐8 and TNF‐α in AGS cells, and the fold increase was much higher than that in HEp‐2 cells. Our results demonstrate proinflammatory and cytotoxic role of C. braakii in gastric epithelial cells, indicating the bacterium is potentially involved in inducing gastric mucosa inflammation. [ABSTRACT FROM AUTHOR]

The article presents abstracts of research papers about the effects of neuroinflammation on gap junction communication. They include "Connexins and neuroprotection: minding the gap," "Connexins regulate gene expression: how, why, and implications for neuroinflammation," "Astrocyte gap junctions are a target for pro-inflammatory cytokines released from microglial cells," and "The gram-positive bacterium S. aureus differentially modulates gap junction communication in astrocytes and microglia."

In 2023, the Antimicrobial Peptide Database (currently available at https://aps.unmc.edu) is 20‐years‐old. The timeline for the APD expansion in peptide entries, classification methods, search functions, post‐translational modifications, binding targets, and mechanisms of action of antimicrobial peptides (AMPs) has been summarized in our previous Protein Science paper. This article highlights new database additions and findings. To facilitate antimicrobial development to combat drug‐resistant pathogens, the APD has been re‐annotating the data for antibacterial activity (active, inactive, and uncertain), toxicity (hemolytic and nonhemolytic AMPs), and salt tolerance (salt sensitive and insensitive). Comparison of the respective desired and undesired AMP groups produces new knowledge for peptide design. Our unification of AMPs from the six life kingdoms into "natural AMPs" enabled the first comparison with globular or transmembrane proteins. Due to the dominance of amphipathic helical and disulfide‐linked peptides, cysteine, glycine, and lysine in natural AMPs are much more abundant than those in globular proteins. To include peptides predicted by machine learning, a new "predicted" group has been created. Remarkably, the averaged amino acid composition of predicted peptides is located between the lower bound of natural AMPs and the upper bound of synthetic peptides. Synthetic peptides in the current APD, with the highest cationic and hydrophobic amino acid percentages, are mostly designed with varying degrees of optimization. Hence, natural AMPs accumulated in the APD over 20 years have laid the foundation for machine learning prediction. We discuss future directions for peptide discovery. It is anticipated that the APD will continue to play a role in research and education. [ABSTRACT FROM AUTHOR]

Defensins and inflammation are innate immune barriers of the body against infectious pathogens. Searching for a compound that can inhibit infectious diseases by affecting human β‐defensin (HBD) and proinflammatory cytokines is the new trend in research to control bacterial infection. The aim of this study is to provide a natural compound, Filipendula glaberrima Nakai extract (FGE), which is able to induce the expression of an antimicrobial defensin as well as reduce inflammation. FGE induced the expression of HBD2 and HBD3 through activating both p38 and NF‐κB signaling pathways. Furthermore, FGE inhibited the expression of TNF‐α and IL‐6 via p38 and NF‐κB pathways in Staphylococcus aureus–stimulated THP1 cells. Injection of FGE alleviated cutaneous erythema and swelling caused by S. aureus injection in mice ears. Taken together, FGE could reduce bacterial infection by inducing the expression of defensin and anti‐inflammatory activity. [ABSTRACT FROM AUTHOR]

Lysosomal Storage Disorders (LSDs) are a diverse group of inherited, monogenic diseases caused by functional defects in specific lysosomal proteins. The lysosome is a cellular organelle that plays a critical role in catabolism of waste products and recycling of macromolecules in the body. Disruption to the normal function of the lysosome can result in the toxic accumulation of storage products, often leading to irreparable cellular damage and organ dysfunction followed by premature death. The majority of LSDs have no curative treatment, with many clinical subtypes presenting in early infancy and childhood. Over two‐thirds of LSDs present with progressive neurodegeneration, often in combination with other debilitating peripheral symptoms. Consequently, there is a pressing unmet clinical need to develop new therapeutic interventions to treat these conditions. The blood–brain barrier is a crucial hurdle that needs to be overcome in order to effectively treat the central nervous system (CNS), adding considerable complexity to therapeutic design and delivery. Enzyme replacement therapy (ERT) treatments aimed at either direct injection into the brain, or using blood–brain barrier constructs are discussed, alongside more conventional substrate reduction and other drug‐related therapies. Other promising strategies developed in recent years, include gene therapy technologies specifically tailored for more effectively targeting treatment to the CNS. Here, we discuss the most recent advances in CNS‐targeted treatments for neurological LSDs with a particular emphasis on gene therapy‐based modalities, such as Adeno‐Associated Virus and haematopoietic stem cell gene therapy approaches that encouragingly, at the time of writing are being evaluated in LSD clinical trials in increasing numbers. If safety, efficacy and improved quality of life can be demonstrated, these therapies have the potential to be the new standard of care treatments for LSD patients. [ABSTRACT FROM AUTHOR]

Glycolipid balance is key to normal body function, and its alteration can lead to a variety of diseases involving multiple organs and tissues. Glycolipid disturbances are also involved in Parkinson's disease (PD) pathogenesis and aging. Increasing evidence suggests that glycolipids affect cellular functions beyond the brain, including the peripheral immune system, intestinal barrier, and immunity. Hence, the interplay between aging, genetic predisposition, and environmental exposures could initiate systemic and local glycolipid changes that lead to inflammatory reactions and neuronal dysfunction. In this review, we discuss recent advances in the link between glycolipid metabolism and immune function and how these metabolic changes can exacerbate immunological contributions to neurodegenerative diseases, with a focus on PD. Further understanding of the cellular and molecular mechanisms that control glycolipid pathways and their impact on both peripheral tissues and the brain will help unravel how glycolipids shape immune and nervous system communication and the development of novel drugs to prevent PD and promote healthy aging. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSCs) are an immature group of myeloid‐derived cells generated from myeloid cell precursors in the bone marrow. MDSCs appear almost exclusively in pathological conditions, such as tumor progression and various inflammatory diseases. The leading function of MDSCs is their immunosuppressive ability, which plays a crucial role in tumor progression and metastasis through their immunosuppressive effects. Since MDSCs have specific molecular features, and only a tiny amount exists in physiological conditions, MDSC‐targeted therapy has become a promising research direction for tumor treatment with minimal side effects. In this review, we briefly introduce the classification, generation and maturation process, and features of MDSCs, and detail their functions under various circumstances. The present review specifically demonstrates the environmental specificity of MDSCs, highlighting the differences between MDSCs from cancer and healthy individuals, as well as tumor‐infiltrating MDSCs and circulating MDSCs. Then, we further describe recent advances in MDSC‐targeted therapies. The existing and potential targeted drugs are divided into three categories, monoclonal antibodies, small‐molecular inhibitors, and peptides. Their targeting mechanisms and characteristics have been summarized respectively. We believe that a comprehensive in‐depth understanding of MDSC‐targeted therapy could provide more possibilities for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Chronic pain and opioid use disorder (OUD) are major public health problems, with rising opioid-related overdose deaths linked to increased opioid prescriptions for pain management. Novel treatment approaches for these commonly comorbid disorders are needed. Growing evidence supports a role for glial activation for both chronic pain and substance use disorders, including OUD. This review provides an overview of glial modulators as a novel treatment approach for comorbid pain and OUD. We aim to synthesize clinical studies investigating the efficacy of glial modulators in treating these comorbid disorders. We conducted a literature search of PubMed and Google Scholar databases in October 2023 to identify relevant clinical trials. The included studies varied in terms of patient population, study methodology and outcomes assessed, and were often limited by small sample sizes and other methodological issues. Additionally, several glial modulators have yet to be studied for chronic pain and OUD. Despite these limitations, these studies yielded positive signals that merit further investigation. Both chronic pain and OUD remain significant public health problems, with many treatment challenges. Glial modulators continue to hold promise as novel therapeutics for comorbid pain and OUD, given positive indications that they can improve pain measures, and reduce addiction-related outcomes. As our understanding of the mechanisms underlying the contributions of glial modulators to pain and addiction behaviours deepens, we will be better equipped to identify more specific therapeutic targets for chronic pain and OUD., (© 2024 British Pharmacological Society.)

In the last two decades, the term synaptopathy has been largely used to underline the concept that impairments of synaptic structure and function are the major determinant of brain disorders, including neurodevelopmental disorders. This notion emerged from the progress made in understanding the genetic architecture of neurodevelopmental disorders, which highlighted the convergence of genetic risk factors onto molecular pathways specifically localized at the synapse. However, the multifactorial origin of these disorders also indicated the key contribution of environmental factors. It is well recognized that inflammation is a risk factor for neurodevelopmental disorders, and several immune molecules critically contribute to synaptic dysfunction. In the present review, we highlight this concept, which we define by the term "immune‐synaptopathy," and we discuss recent evidence suggesting a bi‐directional link between the genetic architecture of individuals and maternal activation of the immune system in modulating brain developmental trajectories in health and disease. [ABSTRACT FROM AUTHOR]

Age‐related immune dysfunctions, such as decreased T‐cell output, are closely related to pathologies like cancers and lack of vaccine efficacy among the elderly. Engineered fusokine, GIFT‐7, a fusion of interleukin 7 (IL‐7) and GM‐CSF, can reverse aging‐related lymphoid organ atrophy. We generated a GIFT‐7 fusokine tumor vaccine and employed it in aged syngeneic mouse models of glioblastoma and found that peripheral vaccination with GIFT‐7TVax resulted in thymic regeneration and generated durable long‐term antitumor immunity specifically in aged mice. Global cytokine analysis showed increased pro‐inflammatory cytokines including IL‐1β in the vaccinated group that resulted in hyperactivation of dendritic cells. In addition, GIFT‐7 vaccination resulted in increased T‐cell trafficking to the brain and robust Th‐17 long‐term effector memory T‐cell formation. TCR‐seq analysis showed increased productive frequency among detected rearrangements within the vaccinated group. Overall, our data demonstrate that aging immune system can be therapeutically augmented to generate lasting antitumor immunity. [ABSTRACT FROM AUTHOR]

Changes in synaptic function are an early hallmark of neuropathological conditions that often precede symptom onset, with mounting genetic, transcriptional, and epidemiological evidence implicating microglia in this process. The correlation between infection and neurocognitive sequelae further suggests that environmental exposures modulate neuroimmune interactions and contribute to synaptic alterations. Recent studies investigating functional roles of microglia across broad neuropathological contexts including neurodegeneration, aging, neuropsychiatric and neurodevelopmental disorders, and neurotropic infections reveal convergent mechanisms underlying microglial‐mediated synaptic dysfunction. We propose that early microglial changes, driven by genetic alterations coupled with environmental neuroimmune modulation, may be a common denominator that contributes to early synaptic pathologies. Here we review the evidence and discuss how microglia respond, and contribute, to synaptopathies across diverse neurological conditions, spotlighting their importance as broadly relevant therapeutic targets within neurological diseases. [ABSTRACT FROM AUTHOR]

Late‐infantile neuronal ceroid lipofuscinosis (LINCL) and juvenile neuronal ceroid lipofuscinosis (JNCL) are inherited neurodegenerative diseases caused by mutations in the genes encoding lysosomal proteins tripeptidyl peptidase 1 (TPP1) and CLN3 protein, respectively. TPP1 is well‐understood and, aided by animal models that accurately recapitulate the human disease, enzyme replacement therapy has been approved and other promising therapies are emerging. In contrast, there are no effective treatments for JNCL, partly because the function of the CLN3 protein remains unknown but also because animal models have attenuated disease and lack robust survival phenotypes. Mouse models for LINCL and JNCL, with mutations in Tpp1 and Cln3, respectively, have been thoroughly characterized but the phenotype of a double Cln3/Tpp1 mutant remains unknown. We created this double mutant and find that its phenotype is essentially indistinguishable from the single Tpp1−/− mutant in terms of survival and brain pathology. Analysis of brain proteomic changes in the single Tpp1−/− and double Cln3−/−;Tpp1−/− mutants indicates largely overlapping sets of altered proteins and reinforces earlier studies that highlight GPNMB, LYZ2, and SERPINA3 as promising biomarker candidates in LINCL while several lysosomal proteins including SMPD1 and NPC1 appear to be altered in the Cln3−/− animals. An unexpected finding was that Tpp1 heterozygosity significantly decreased lifespan of the Cln3−/− mouse. The truncated survival of this mouse model makes it potentially useful in developing therapies for JNCL using survival as an endpoint. In addition, this model may also provide insights into CLN3 protein function and its potential functional interactions with TPP1. [ABSTRACT FROM AUTHOR]

Septic arthritis is a joint disease caused by Staphylococcus aureus. Different macrophage populations contribute in various ways to control blood‐borne infections and induce inflammatory responses. Macrophage tissue–resident niche is necessary for the suppression of chronic inflammation and may contribute to the pathogenesis of septic arthritis. Thus, to obtain a resolution of the disease and restoration of synovial homeostasis, it needs the activation of macrophages that further regulate the inflammatory consequences. The aim of this study was to find out the mechanism by which neutralization of transforming growth factor‐beta (TGF‐β) and/or interleukin (IL)‐6 after induction of septic arthritis could alter the specific macrophage responses in spleen and synovial joints via different cytokines (osteoprotegerin (OPG), osteopontin (OPN), IL‐10, IL‐12 and CXCL8) cross‐talking, and how the response could be modulated by reactive oxygen species vs antioxidant enzyme activities. Dual neutralization of TGF‐β and IL‐6 is notably effective in eliciting splenic and synovial tissue–resident macrophage responses. Synovial macrophage‐derived IL‐10 can elicit protection against septic arthritis via regulating receptor‐activated nuclear factor Kappa‐B ligand (RANKL)/OPG interaction. They also reduced oxidative stress by increasing the activity of antioxidant enzymes including SOD and catalase. Histopathological analysis revealed that dual neutralization of TGF‐β and IL‐6 prevented bone destruction and osteoclastic activity in septic arthritis by promoting the differential functional response of the splenic and synovial macrophages. Additionally, the macrophage‐derived IL‐10 can elicit protection against S. aureus‐induced septic arthritis via regulating RANKL/OPG interaction. Further studies on STAT3 and STAT4 are needed for the understanding of such cross‐talking in resident macrophages of arthritic mice. [ABSTRACT FROM AUTHOR]

Background: Diabetic cognitive dysfunction (DCD) is one of the most insidious complications of type 2 diabetes mellitus, which can seriously affect the ability to self‐monitoring of blood glucose and the quality of life in the elderly. Previous pathological studies of cognitive dysfunction have focused on neuronal dysfunction, characterized by extracellular beta‐amyloid deposition and intracellular tau hyperphosphorylation. In recent years, astrocytes have been recognized as a potential therapeutic target for cognitive dysfunction and important participants in the central control of metabolism. The disorder of gut microbiota and their metabolites have been linked to a series of metabolic diseases such as diabetes mellitus. The imbalance of intestinal flora has the effect of promoting the occurrence and deterioration of several diabetes‐related complications. Gut microbes and their metabolites can drive astrocyte activation. Aims: We reviewed the pathological progress of DCD related to the "gut microbiota‐astrocyte" axis in terms of peripheral and central inflammation, intestinal and blood–brain barrier (BBB) dysfunction, systemic and brain energy metabolism disorders to deepen the pathological research progress of DCD and explore the potential therapeutic targets. Conclusion: "Gut microbiota‐astrocyte" axis, unique bidirectional crosstalk in the brain‐gut axis, mediates the intermediate pathological process of neurocognitive dysfunction secondary to metabolic disorders in diabetes mellitus. [ABSTRACT FROM AUTHOR]

A dysfunctional epidermal barrier, which may be associated with mutations in the filaggrin gene in genetically predisposed individuals or harmful effects of environmental agents and allergens, contributes to the development of atopic dermatitis (AD) due to an interplay between the epithelial barrier, immune defence and the cutaneous microbiome. The skin of patients with AD is frequently over‐colonized by biofilm‐growing Staphylococcus aureus, especially during flares, causing dysbiosis of the cutaneous microbiota and a decrease in bacterial diversity that inversely correlates with AD severity. Specific changes in the skin microbiome can be present before clinical AD onset in infancy. Additionally, local skin anatomy, lipid content, pH, water activity and sebum secretion differ between children and adults and generally correlate with the predominant microbiota. Considering the importance of S. aureus in AD, treatments aimed at reducing over‐colonization to rebalance microbial diversity may help manage AD and reduce flares. Anti‐staphylococcal interventions in AD will contribute to a decrease in S. aureus superantigens and proteases that cause damage and inflammation of the skin barrier while concomitantly increasing the proportion of commensal bacteria that secrete antimicrobial molecules that protect healthy skin from invading pathogens. This review summarizes the latest data on targeting skin microbiome dysbiosis and S. aureus over‐colonization to treat AD in adults and children. Indirect AD therapies, including emollients 'plus', anti‐inflammatory topicals and monoclonal antibodies, may have an impact on S. aureus and help control bacterial diversity. Direct therapies, including antibacterial treatments (antiseptics/topical or systemic antibiotics), and innovative treatments specifically targeting S. aureus (e.g. anti‐S. aureus endolysin, and autologous bacteriotherapy), may be effective alternatives to mitigate against an increase in microbial resistance and allow a proportionate increase in the commensal microbiota. [ABSTRACT FROM AUTHOR]

Toll‐like receptors (TLRs) are a family of pattern‐recognition receptors triggered by pathogen‐derived and tissue‐damage‐related ligands. TLRs were previously believed to only be expressed in immune cells. However, it is now confirmed that they are ubiquitously expressed in cells within the body including neurons, astrocytes, and microglia of the central nervous system (CNS). Activation of TLRs is capable of inducing immunologic and inflammatory responses to injury or infection of CNS. This response is self‐limiting that usually resolves once the infection has been eradicated or the tissue damage has been repaired. However, the persistence of inflammation‐inducing insults or a failure in normal resolution mechanisms may result in overwhelming inflammation which may induce neurodegeneration. This implies that TLRs may play a role in mediating the link between inflammation and neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. So, new therapeutic approaches that specifically target TLRs may be developed by better understanding TLR expression mechanisms in the CNS and their connections to particular neurodegenerative disorders. Therefore, this review paper discussed the role of TLRs in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to explore the effect of periodontitis on Th‐cell subsets in local and systemic environments. Methods: A total of 32 male Sprague‒Dawley rats were randomly divided into periodontitis and control groups. Silk ligatures were applied to the mandibular first (M1) molars in the periodontitis group. Inflammation and alveolar bone loss around the M1 molars were analyzed by histological staining and microcomputed tomography. The mRNA expression of interferon‐γ (IFN‐γ), interleukin 4 (IL‐4), IL‐17, and IL‐10 in the gingiva was measured by qRT‐PCR. The proportions of Th1, Th2, Th17, and Treg cells in the submandibular lymph nodes, peripheral blood, and jaw bone marrow were tested using flow cytometry. Results: More inflammatory cells and alveolar bone resorption were found in the periodontitis group, with upregulated mRNA expression of IFN‐γ, IL‐17, and IL‐10. The proportion of Th1 and Th17 cells was significantly elevated in submandibular lymph nodes, and the proportion of Th1, Th2, and Th17 cells was significantly elevated in peripheral blood, while the proportion of Th1, Th17, and Treg cells was significantly elevated in jaw bone marrow in the periodontitis group. Conclusion: This study suggests that periodontitis affects the differentiation of Th‐cell subsets in both local and systemic environments, resulting in an increased proportion of proinflammatory cells. [ABSTRACT FROM AUTHOR]

Lactate, once recognized as a wasty product from anaerobic glycolysis, is proved to be a pivotal signal molecule. Lactate accumulation occurs in diverse physiological and pathological settings due to the imbalance between lactate production and clearance. Under the condition with drastic changes in local microenvironment, such as tumorigenesis, inflammation, and microbial infection, the glycolysis turns to be active in surrounding cells leading to increased lactate release. Meanwhile, lactate can be utilized by these cells as an energy substrate and acts as a signal molecule to regulate cell functions through receptor‐dependent or independent pathways. In this review, we tended to tease out the contribution of lactate in tumor progression and immunomodulation. And we also discussed the accessory role of lactate, beyond as the energy source only, in the growth of invading pathogens. [ABSTRACT FROM AUTHOR]

Bibliometric analyses are often used as a means of visualising the knowledge base and associated trends and patterns in a target scientific field based on a quantitative review of the corresponding literature. In this study, we explore the current status of research pertaining to biofilms in wound healing and elucidate trends in this research space. Through this process, we gain insight into findings from papers indexed in the Web of Science Core Collection. These references were then analysed and plotted using Microsoft Excel 2019, VOSviewer, and CiteSpace V. The results provide a fresh perspective regarding global trends and hotspots in biofilm‐related wound healing research. These findings also offer a foundation that researchers can use to identify active hotspots of scientific interest to guide further research endeavours. [ABSTRACT FROM AUTHOR]

Macrophage migration inhibitory factor (MIF) is a pro‐inflammatory cytokine that represents a link between diet‐induced inflammation and insulin resistance. Our aim was to examine whether fructose diet affects inflammation and insulin signaling in the prefrontal cortex (PFC) of Mif knockout mice (MIF‐KO), and their possible link to neural plasticity and behavior. We analyzed nuclear factor κB (NF‐κB) and glucocorticoid signaling, expression of F4/80, IL‐1β, TNF‐α, TLR‐4, MyD88, arginase 1 (Arg‐1), mannose receptor (Mrc‐1), and leukemia inhibitory factor (Lif) to assess inflammation in the PFC of C57/BL6J and MIF‐KO mice consuming 20% fructose solution for 9 weeks. Insulin receptor (IR), IRS‐1 serine phosphorylations (307 and 1101) and activity of PKCα, Akt, GSK‐3β and AMPKα were used to analyze insulin signaling. Brain‐derived neurotrophic factor (BDNF) and insulin‐like growth factor 1 (IGF‐1) mRNA levels, together with synapthophysin and PSD‐95 protein level and calcium calmodulin‐dependent kinase 2 (CaMKII) activity, were used as plasticity markers. Behavior was examined in elevated plus maze, light dark box and novel object recognition test. The results showed concomitant increase of Tnf‐α, Tlr‐4, MyD88 and M2 microglia markers (Arg‐1, Mrc‐1, Lif) in the PFC of MIF‐KO, paralleled with unchanged glucocorticoid and insulin signaling. Increase of BDNF and IGF‐1 was paralleled with increased CaMKII activity, decreased PSD‐95 protein level, anxiogenic behavior, and impaired memory in MIF‐KO mice. Fructose feeding restored these parameters in the PFC to the control level and mitigated behavioral changes, suggesting that ameliorating effects of fructose on neuroinflammation and behavior depend on the presence of MIF. [ABSTRACT FROM AUTHOR]

Inflammation associated with viral infection of the nervous system has been involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis. Polyinosinic:polycytidylic acid (poly[I:C]) is a Toll‐like receptor 3 (TLR3) agonist that mimics the inflammatory response to systemic viral infections. Despite growing recognition of the role of glial cells in AD pathology, their involvement in the accumulation and clearance of amyloid β (Aβ) in the brain of patients with AD is poorly understood. Neprilysin (NEP) and insulin‐degrading enzyme (IDE) are the main Aβ‐degrading enzymes in the brain. This study investigated whether poly(I:C) regulated Aβ degradation and neurotoxicity by modulating NEP and IDE protein levels through TLR3 in astrocytes. To this aim, primary rat primary astrocyte cultures were treated with poly(I:C) and inhibitors of the TLR3 signaling. Protein levels were assessed by Western blot. Aβ toxicity to primary neurons was measured by lactate dehydrogenase release. Poly(I:C) induced a significant decrease in NEP levels on the membrane of astrocytes as well as in the culture medium. The degradation of exogenous Aβ was markedly delayed in poly(I:C)‐treated astrocytes. This delay significantly increased the neurotoxicity of exogenous Aβ1‐42. Altogether, these results suggest that viral infections induce Aβ neurotoxicity by decreasing NEP levels in astrocytes and consequently preventing Aβ degradation. [ABSTRACT FROM AUTHOR]

Periprosthetic joint infections (PJI) induce an immunosuppressive cytokine profile through an unknown mechanism. Immune checkpoints, like programmed cell death 1 (PD‐1) and its ligand (PD‐L1), initiate innate immunosuppressive pathways essential for self‐tolerance. Several malignancies and chronic infections co‐opt these pathways to derive a survival advantage. This study evaluates PD‐1/PD‐L1 expression in periprosthetic tissue from patients undergoing revision hip or knee arthroplasty for a PJI versus an aseptic failure. PD‐1/PD‐L1 in the global tissue sample and the high‐power microscopic field of maximum expression was analyzed prospectively using immunohistochemistry. Fifteen patients with a PJI (45%) and 16 patients with an aseptic failure (52%) were included. PD‐1 expression was uniformly low. Maximum PD‐L1 expression was upregulated in patients with a PJI (25%, interquartile range [IQR]: 5%–75%) versus an aseptic failure, (8%, IQR: 1%–48%, p = 0.039). In the PJI cohort, maximum PD‐L1 expression was higher among patients who developed a recurrent PJI (68%, IQR: 53%–86% vs. 15%, IQR: 5%–70%, p = 0.039). Patients with global PD‐L1 over 5% trended toward a near 22‐fold increase in the odds of reinfection (odds ratio [OR]: 21.9, 95% confidence interval [CI]: 0.9–523.5, p = 0.057) and patients with maximum PD‐L1 over 20% trended toward a 15‐fold increase in the odds of reinfection (OR: 15.0, 95% CI: 0.6–348.9, p = 0.092). These results support immune checkpoint upregulation as a mechanism of PJI‐induced local immune dysfunction. Future studies should confirm PD‐L1 as a risk factor for reinfection in larger cohorts. [ABSTRACT FROM AUTHOR]

Lysosomal storage disorders (LSDs) are inherited metabolic diseases caused by genetic defects in lysosomal enzymes or related factors. LSDs are associated with excessive accumulation of natural substrates in lysosomes leading to central nervous system and peripheral tissue damage. Abnormal autophagy is also involved in pathogenesis, although the underlying mechanisms remain unclear. We demonstrated that impairment of lysosome‐autophagosome fusion is due to suppressed endocytosis in LSDs. The fusion was reduced in several LSD cells and the brains of LSD model mice, suggesting that the completion of autophagy is suppressed by the accumulation of substrates. In this brain, the expression of the soluble N‐ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins, VAMP8 and Syntaxin7, was decreased on the lysosomal surface but not intracellular. This aberrant autophagy preceded the development of pathological phenotypes in LSD‐model mice. Furthermore, the enzyme deficiency leading to the substrate accumulation could suppress endocytosis, and the inhibited endocytosis decreased SNARE proteins localized on lysosomes. These findings suggest that the shortage of SNARE proteins on lysosomes is one of the reasons for the impairment of lysosome‐autophagosome fusion in LSD cells. Defects in lysosomal enzyme activity suppress endocytosis and decrease the supply of intracellular SNARE proteins recruited to lysosomes. This shortage of lysosomal SNARE proteins impairs lysosome‐autophagosome fusion in lysosomal storage disorders. [ABSTRACT FROM AUTHOR]

Improved understanding of the bidirectional crosstalk between peripherally derived immune cells and CNS-resident cells will be key to the development of improved strategies to treat MS and many other forms of neurological disease. Neurodegenerative disorders, which include Alzheimer's disease, ALS, and Parkinson's disease, are devastating neurological conditions that are broadly characterized by neuronal cell death, neuroinflammation, and progressive loss of proper neurological function. A deeper understanding of how epigenetic alterations shape the immune landscape during CNS pathogen invasion can have significant therapeutic implications for a number of infections that pose a significant threat to the CNS. For decades, the brain was thought to be an immune-privileged organ that was physically separated from the immune system in a strategic effort to limit potentially deleterious actions of immune signaling on the central nervous system (CNS). [Extracted from the article]

Fungal infections in the central nervous system (CNS) cause high morbidity and mortality. The frequency of CNS mycosis has increased over the last two decades as more individuals go through immunocompromised conditions for various reasons. Nevertheless, options for clinical interventions for CNS mycoses are still limited. Thus, there is an urgent need to understand the host–pathogen interaction mechanisms in CNS mycoses for developing novel treatments. Although the CNS has been regarded as an immune‐privileged site, recent studies demonstrate the critical involvement of immune responses elicited by CNS‐resident and CNS‐infiltrated cells during fungal infections. In this review, we discuss mechanisms of fungal invasion in the CNS, fungal pathogen detection by CNS‐resident cells (microglia, astrocytes, oligodendrocytes, neurons), roles of CNS‐infiltrated leukocytes, and host immune responses. We consider that understanding host immune responses in the CNS is crucial for endeavors to develop treatments for CNS mycosis. [ABSTRACT FROM AUTHOR]

Epigenetics involves the study of various modes of adaptable transcriptional regulation, contributing to cell identity, characteristics, and function. During central nervous system (CNS) infection, epigenetic mechanisms can exert pronounced control over the maturation and antimicrobial properties of nearly every immune cell type. Epigenetics is a relatively new field, with the first mention of these marks proposed only a half‐century ago and a substantial body of immunological epigenetic research emerging only in the last few decades. Here, we review the best‐characterized epigenetic marks and their functions as well as illustrate how various immune cell populations responding to CNS infection utilize these marks to organize their activation state and inflammatory processes. We also discuss the metabolic and clinical implications of epigenetic marks and the rapidly expanding set of tools available to researchers that are enabling elucidation of increasingly detailed genetic regulatory pathways. These considerations paint an intricate picture of inflammatory regulation, where epigenetic marks influence genetic, signaling, and environmental elements to orchestrate a tailored immunological response to the threat at hand, cementing epigenetics as an important player in immunity. [ABSTRACT FROM AUTHOR]

Aim: To provide an overview of clinical, immunological, and mycological aspects of vulvovaginal candidiasis (VVC). Methods: A literature search was conducted to find relevant articles about different aspects of VVC. Related data from retrieved articles were summarized in different headings. Results: VVC has a global distribution and Candida albicans is the leading cause of infection except for specific patient groups like postmenopausal, diabetic, or immunocompromised women. VVC has a range of clinical presentations, accordingly, its diagnosis should be based on clinical examination coupled with laboratory investigations. The best therapeutic regimen depends on the patient's conditions and the causative agent. Moreover, factors like drug resistance of the causative agents and different mutations in the immunity‐related genes could affect the treatment outcome. Conclusion: As a globally distributed disease, VVC needs further attention, especially in areas related to the treatment failure and recurrence of the disease. [ABSTRACT FROM AUTHOR]

Periprosthetic joint infection (PJI) remains a devastating complication after total joint arthroplasty. Bacteria involved in these infections are notorious for adhering to foreign implanted surfaces and generating a biofilm matrix. These biofilms protect the bacteria from antibiotic treatment and the immune system making eradication difficult. Current treatment strategies including debridement, antibiotics, and implant retention, and one‐ and two‐stage revisions still present a relatively high overall failure rate. One of the main shortcomings that has been associated with this high failure rate is the lack of a robust approach to treating bacterial biofilm. Therefore, in this review, we will highlight new strategies that have the potential to combat PJI by targeting biofilm integrity, therefore giving antibiotics and the immune system access to the internal network of the biofilm structure. This combination antibiofilm/antibiotic therapy may be a new strategy for PJI treatment while promoting implant retention. [ABSTRACT FROM AUTHOR]

Background: Dysregulation of innate and adaptive immunity heralds both the development and progression of Parkinson's disease (PD). Deficits in innate immunity in PD are defined by impairments in monocyte activation, function, and pro‐inflammatory secretory factors. Each influences disease pathobiology. Methods and Results: To define monocyte biomarkers associated with immune transformative therapy for PD, changes in gene and protein expression were evaluated before and during treatment with recombinant human granulocyte‐macrophage colony‐stimulating factor (GM‐CSF, sargramostim, Leukine®). Monocytes were recovered after leukapheresis and isolation by centrifugal elutriation, before and 2 and 6 months after initiation of treatment. Transcriptome and proteome biomarkers were scored against clinical motor functions. Pathway enrichments from single cell‐RNA sequencing and proteomic analyses from sargramostim‐treated PD patients demonstrate a neuroprotective signature, including, but not limited to, antioxidant, anti‐inflammatory, and autophagy genes and proteins (LRRK2, HMOX1, TLR2, TLR8, RELA, ATG7, and GABARAPL2). Conclusions: This monocyte profile provides an "early" and unique biomarker strategy to track clinical immune‐based interventions, but requiring validation in larger case studies. [ABSTRACT FROM AUTHOR]

Microglia, the resident immune cells in the retina and nervous system, make irreplaceable contributions to the maintenance of normal homeostasis and immune surveillance of these systems. Recently, great progress has been made in determining the origin, distribution, features and functions of retinal microglia and in identifying their roles in retinal diseases. In the retinal microenvironment, microglia constantly monitor changes in their surroundings and maintain balanced functions by communicating with other retinal cells. When disturbed, activated microglia may kill degenerated neurons and photoreceptors through phagocytosis and exacerbate retinal injury by producing multiple proinflammatory mediators. Numerous animal studies and in situ analyses of human tissue have shown that retinal microglia are involved in multiple retinal diseases. The functions and mechanisms of activated microglia in retinal disorders are gradually being elucidated. Increasing evidence points towards the dual roles of microglia in the retina and they are regulated by many factors. How to inhibit the detrimental effects of microglia and promote beneficial effects are worth studying. This review focuses primarily on the features and functions of microglia and how they participate in retinal diseases based on existing research findings. We also discuss current opinions about microglial transdifferentiation. [ABSTRACT FROM AUTHOR]

Mammalian innate immunity employs several humoral 'weapons' that target the bacterial envelope. The threats posed by the multidrug‐resistant 'ESKAPE' Gram‐negative pathogens (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are forcing researchers to explore new therapeutic options, including the use of these immune elements. Here we review bacterial envelope‐targeting (peptidoglycan and/or membrane‐targeting) proteins/peptides of the mammalian immune system that are most likely to have therapeutic applications. Firstly we discuss their general features and protective activity against ESKAPE Gram‐negatives in the host. We then gather, integrate, and discuss recent research on experimental therapeutics harnessing their bactericidal power, based on their exogenous administration and also on the discovery of bacterial and/or host targets that improve the performance of this endogenous immunity, as a novel therapeutic concept. We identify weak points and knowledge gaps in current research in this field and suggest areas for future work to obtain successful envelope‐targeting therapeutic options to tackle the challenge of antimicrobial resistance. [ABSTRACT FROM AUTHOR]

Inactivating mutations in the PPT1 gene encoding palmitoyl‐protein thioesterase‐1 (PPT1) underlie the CLN1 disease, a devastating neurodegenerative lysosomal storage disorder. The mechanism of pathogenesis underlying CLN1 disease has remained elusive. PPT1 is a lysosomal enzyme, which catalyzes the removal of palmitate from S‐palmitoylated proteins (constituents of ceroid lipofuscin) facilitating their degradation and clearance by lysosomal hydrolases. Thus, it has been proposed that Ppt1‐deficiency leads to lysosomal accumulation of ceroid lipofuscin leading to CLN1 disease. While S‐palmitoylation is catalyzed by palmitoyl acyltransferases (called ZDHHCs), palmitoyl‐protein thioesterases (PPTs) depalmitoylate these proteins. We sought to determine the mechanism by which Ppt1‐deficiency may impair lysosomal degradative function leading to infantile neuronal ceroid lipofuscinosis pathogenesis. Here, we report that in Ppt1−/− mice, which mimic CLN1 disease, low level of inositol 3‐phosphate receptor‐1 (IP3R1) that mediates Ca++ transport from the endoplasmic reticulum to the lysosome dysregulated lysosomal Ca++ homeostasis. Intriguingly, the transcription factor nuclear factor of activated T‐cells, cytoplasmic 4 (NFATC4), which regulates IP3R1‐expression, required S‐palmitoylation for trafficking from the cytoplasm to the nucleus. We identified two palmitoyl acyltransferases, ZDHHC4 and ZDHHC8, which catalyzed S‐palmitoylation of NFATC4. Notably, in Ppt1−/− mice, reduced ZDHHC4 and ZDHHC8 levels markedly lowered S‐palmitoylated NFATC4 (active) in the nucleus, which inhibited IP3R1‐expression, thereby dysregulating lysosomal Ca++ homeostasis. Consequently, Ca++‐dependent lysosomal enzyme activities were markedly suppressed. Impaired lysosomal degradative function impaired autophagy, which caused lysosomal storage of undigested cargo. Importantly, IP3R1‐overexpression in Ppt1−/− mouse fibroblasts ameliorated this defect. Our results reveal a previously unrecognized role of Ppt1 in regulating lysosomal Ca++ homeostasis and suggest that this defect contributes to pathogenesis of CLN1 disease. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus causes severe infections associated with inflammation, such as sepsis or osteomyelitis. Inflammatory processes are regulated by distinct lipid mediators (LMs) but how their biosynthetic pathways are orchestrated in S. aureus infections is elusive. We show that S. aureus strikingly not only modulates pro‐inflammatory, but also inflammation‐resolving LM pathways in murine osteomyelitis and osteoclasts as well as in human monocyte‐derived macrophages (MDMs) with different phenotype. Targeted LM metabololipidomics using ultra‐performance liquid chromatography‐tandem mass spectrometry revealed massive generation of LM with distinct LM signature profiles in acute and chronic phases of S. aureus‐induced murine osteomyelitis in vivo. In human MDM, S. aureus elevated cyclooxygenase‐2 (COX‐2) and microsomal prostaglandin E2 synthase‐1 (mPGES‐1), but impaired the levels of 15‐lipoxygenase‐1 (15‐LOX‐1), with respective changes in LM signature profiles initiated by these enzymes, that is, elevated PGE2 and impaired specialized pro‐resolving mediators, along with reduced M2‐like phenotypic macrophage markers. The cell wall component, lipoteichoic acid (LTA), mimicked the impact of S. aureus elevating COX‐2/mPGES‐1 expression via NF‐κB and p38 MAPK signalling in MDM, while the impairment of 15‐LOX‐1 correlates with reduced expression of Lamtor1. In conclusion, S. aureus dictates LM pathways via LTA resulting in a shift from anti‐inflammatory M2‐like towards pro‐inflammatory M1‐like LM signature profiles. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells' (MSC) therapeutic potential has been investigated for the treatment of several neurodegenerative diseases. The fact these cells can mediate a beneficial effect in different neurodegenerative contexts strengthens their competence to target diverse mechanisms. On the other hand, distinct disorders may share similar mechanisms despite having singular neuropathological characteristics. Methods: We have previously shown that MSC can be beneficial for two disorders, one belonging to the groups of Lysosomal Storage Disorders (LSDs) – the Krabbe Disease or Globoid Cell Leukodystrophy, and the other to the family of Polyglutamine diseases (PolyQs) – the Machado‐Joseph Disease or Spinocerebellar ataxia type 3. We gave also input into disease characterization since neuropathology and MSC's effects are intrinsically associated. This review aims at describing MSC's multimode of action in these disorders while emphasizing to possible mechanistic alterations they must share due to the accumulation of cellular toxic products. Results: Lysosomal storage disorders and PolyQs have different aetiology and associated symptoms, but both result from the accumulation of undegradable products inside neuronal cells due to inefficient clearance by the endosomal/lysosomal pathway. Moreover, numerous cellular mechanisms that become compromised latter are also shared by these two disease groups. Conclusions: Here, we emphasize MSC's effect in improving proteostasis and autophagy cycling turnover, neuronal survival, synaptic activity and axonal transport. LSDs and PolyQs, though rare in their predominance, collectively affect many people and require our utmost dedication and efforts to get successful therapies due to their tremendous impact on patient s' lives and society. [ABSTRACT FROM AUTHOR]

Staphyloccocus aureus is one of the major pathogens in orthopedic periprosthetic joint infection (PJI), a devastating complication of total joint arthroplasty that often results in chronic and persistent infections that are refractory to antibiotics and require surgical interventions. Biofilm formation has been extensively investigated as a reason for persistent infection. The cellular composition, activation status, cytokine profile, and role of the immune response during persistent S. aureus PJI are incompletely understood. In this study, we used histology, multiparametric flow cytometry, and gene expression analysis to characterize the immune response in a clinically relevant orthopedic PJI model. We tested the hypothesis that persistent S. aureus infection induces feedback mechanisms that suppress immune cell activation, thereby affecting the course of infection. Surprisingly, persistent infection was characterized by strikingly high cytokine gene expression indicative of robust activation of multiple components of innate and adaptive immunity, along with ongoing severe neutrophil‐dominated inflammation, in infected joint and bone tissues. Activation and expansion of draining lymph nodes and a bone marrow stress granulopoiesis reaction were also maintained during late phase infection. In parallel, feedback mechanisms involving T‐cell inhibitory receptors and exhaustion markers, suppressive cytokines, and regulatory T cells were activated and associated with decreased T‐cell proliferation and tissue infiltration during the persistent phase of infection. These results identify the cellular and molecular components of the mouse immune response to persistent S. aureus PJI and indicate that neutrophil infiltration, inflammatory cytokine responses, and ongoing lymph node and bone marrow reactions are insufficient to clear infection and that immune effector mechanisms are suppressed by feedback inhibitory pathways. These immune‐suppressive mechanisms are associated with diminished T‐cell proliferation and tissue infiltration and can be targeted as part of adjuvant immunotherapeutic strategies in combination with debridement of biofilm, antibiotics, and other therapeutic modalities to promote eradication of infection. © 2021 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]