The Role of Fibroblasts Across Inflammation and Immunity.

Adipose tissue, adipokines, and inflammation

Simple SummaryOvernutrition, characterized by an excessive caloric intake, often leads to lipotoxicity, a condition where lipids accumulate abnormally in non-adipose tissues. This phenomenon contributes to impaired efferocytosis, the process by which cells remove dead or dying cells, and subsequently triggers chronic inflammation. These interconnected factors serve as precursors to a multitude of disease pathologies. The overabundance of nutrients overwhelms cellular mechanisms, disrupting the delicate balance required for proper efferocytosis. As a result, apoptotic cells linger, perpetuating inflammation and triggering a cascade of detrimental effects on tissue function and homeostasis. Chronic inflammation, a hallmark of various diseases, including cardiovascular disorders, diabetes, and neurodegenerative conditions, underscores the significance of understanding the underlying mechanisms linking overnutrition, impaired efferocytosis, and disease pathogenesis. By elucidating these pathways, researchers aim to develop targeted interventions to mitigate the adverse health outcomes associated with overnutrition-induced lipotoxicity, offering potential avenues for prevention and treatment to combat multifaceted diseases.Overnutrition, driven by the consumption of high-fat, high-sugar diets, has reached epidemic proportions and poses a significant global health challenge. Prolonged overnutrition leads to the deposition of excessive lipids in adipose and non-adipose tissues, a condition known as lipotoxicity. The intricate interplay between overnutrition-induced lipotoxicity and the immune system plays a pivotal role in the pathogenesis of various diseases. This review aims to elucidate the consequences of impaired efferocytosis, caused by lipotoxicity-poisoned macrophages, leading to chronic inflammation and the subsequent development of severe infectious diseases, autoimmunity, and cancer, as well as chronic pulmonary and cardiovascular diseases. Chronic overnutrition promotes adipose tissue expansion which induces cellular stress and inflammatory responses, contributing to insulin resistance, dyslipidemia, and metabolic syndrome. Moreover, sustained exposure to lipotoxicity impairs the efferocytic capacity of macrophages, compromising their ability to efficiently engulf and remove dead cells. The unresolved chronic inflammation perpetuates a pro-inflammatory microenvironment, exacerbating tissue damage and promoting the development of various diseases. The interaction between overnutrition, lipotoxicity, and impaired efferocytosis highlights a critical pathway through which chronic inflammation emerges, facilitating the development of severe infectious diseases, autoimmunity, cancer, and chronic pulmonary and cardiovascular diseases. Understanding these intricate connections sheds light on potential therapeutic avenues to mitigate the detrimental effects of overnutrition and lipotoxicity on immune function and tissue homeostasis, thereby paving the way for novel interventions aimed at reducing the burden of these multifaceted diseases on global health.

Background: The Omicron Variant of Concern (VOC) recently originating from South Africa possesses a striking arrangement of mutations that distinguishes it from prior VOCs and which promotes greatly enhanced transmissibility and evasion from humoral immunity. Methods: To better understand how these mutations have contributed to the “fourth wave” of the pandemic, we assessed 20 Omicron mutant isolates from South Africa against the immunogenetic profile of the South African population. Mutations contributing to innate immune evasion, antibody evasion, and T cell evasion were identified using the VaxiJenv2.0 and NetMHCpan immunoinformatic platforms were catalogued. Results: We characterized an unprecedented number of mutations predicted to cause evasion from innate and adaptive immune elements, including mutations occurring in immunodominant epitopes specific for the South African population. These findings suggest that Omicron’s success stems from its ability to simultaneously evade multiple arms of the immune system at the population level. Conclusion: We report that SARS-CoV variant Omicron appears to have evolved a comprehensive constellation of mutations, enabling it to escape all three arms of the immune system at once. We theorize that this mutational profile is a consequence of slowly adapting on a population with endemic HIV/AIDS, providing the virus the immunological opportunity to evolve more fastidiously on its host.

Purpose: Crohn's disease is a chronic inflammatory bowel disorder associated with a loss of tolerance to commensal gut flora. A phase II clinical trial demonstrated that Sargramostim (recombinant hGM-CSF) was effective in the treatment of patients with moderate-to-severely active Crohn's disease (NEJM 2005; 352:2193–2201). We previously demonstrated that pegylated murine-GM-CSF (pGM) also abrogates colitis in mouse models; effects were blocked by a novel mAb 440c that targets the Siglec-H receptor, unique to plasmacytoid dendritic cells (pDCs). To establish the MOA of GM-CSF in the treatment of Crohn's disease, we investigated GM-CSF effects on 440c+ pDCs, their location in the mucosa, mAb 440c effects on cytokine expression in DSS colitis, and the dependence on adaptive immune elements. Methods: Mice were treated IP with pGM (5ug/d for 5 days), saline, or 22E9 fxn-blocking anti-GM-CSF (200ug) for five days. Splenic cells were analyzed by flow cytometry (CD11c+, 440c+, and B220+ markers). In situ localization was performed by tissue immunohistochemistry (IHC) using mAb 440c. DSS colitis models were performed in Balb/c mice, or RAG1-/- mice, lacking B and T cells, using DSS for 7 days. Groups were treated with PEG-rm-GM-CSF and/or mAb 440c to probe the involvement of the pDC in the response to GM-CSF. Disease activity score, histopathological score, and cytokine expression by real time RT-PCR and protein-arrays were determined. Results: GM-CSF was a potent regulator of the 440c+ pDC (or B220+), with decreases evident in 22E9 treated animals and increases following pGM treatment. pDCs were easily localized by IHC to the subepithelial region of the small intestine and colon. pGM significantly reduced DSS-colitis associated disease activity. However, the administration of mAb 440c blocked this protective effect. Significant decreases in TNFa and IL-1b expression by pGM were blocked by mAb 440c treatment; data further confirmed by protein-array. pGM was therapeutic in RAG1-/- model mice, demonstrating independence from adaptive immune elements. Conclusions: These data suggest that the pDC may play a central role in GM-CSF's therapeutic effects in IBD, and further support a key regulatory role for this small cell population in the mucosal immune response.

The early ontogenetic development of immune cells and organs in teleosts

Macrophages are heterogeneous immune cells with diverse subtypes and tissue-specific distributions, displaying dynamic polarization states that critically govern their immunomodulatory functions and responses to environmental cues. As key regulators of innate and adaptive immunity, they originate from either embryonic progenitors or bone marrow-derived monocytes and exhibit remarkable plasticity in response to microenvironmental cues. Tissue-resident macrophages (e.g., Langerhans cells, Kupffer cells, microglia) display unique organ-specific functions, while inflammatory stimuli drive their polarization into proinflammatory (M1) or anti-inflammatory (M2) phenotypes along a functional continuum. This review systematically examines macrophage subtypes, their anatomical distribution, and the signaling pathways (e.g., NF-κB, STATs, PPARγ) underlying polarization shifts in acute and chronic inflammation. We highlight how polarization imbalances contribute to pathologies including neuroinflammation, liver fibrosis, and impaired tissue repair, particularly in aging contexts. Furthermore, we discuss emerging therapeutic strategies targeting macrophage plasticity, such as cytokine modulation, metabolic reprogramming, and subtype-specific interventions. By integrating recent advances in macrophage biology, this work provides a comprehensive framework for understanding their dual roles in immune regulation and tissue homeostasis, offering insights for treating inflammatory and age-related diseases through macrophage-centered immunomodulation.

Chapter 16 - Role of macrophages in systemic inflammation: wound healing

Methotrexate (MTX) is a frequently utilized anti-inflammatory and anticancer agent. Its potential liver and lung toxicity often limits its clinical effectiveness. We conducted this study to demonstrate the possible protective impacts of a natural galectin-3 (Gal-3) inhibitor, modified citrus pectin (MCP), against MTX-induced liver and lung toxicity and verify the potential signaling pathways of these suggested effects. In vitro, the cytotoxicity of MCP and its modulatory effect on MTX cytotoxic efficacy were assessed. Four groups of rats were used: control, MTX (40mg/kg, single intraperitoneal injection on day 9), MTX + MCP (200mg/kg/day, orally, for 2 weeks), and MCP alone. MCF7, Nalm6, and JEG3 cell lines were used for the in vitro cytotoxicity assay. MCP counteracted liver and lung toxicity evidenced by ameliorating the markers of liver and lung functions. Moreover, MCP minimized oxidative stress elicited by MTX in lung and liver tissues, as indicated by reduced malondialdehyde levels, elevated levels of reduced glutathione, increased superoxide dismutase activity, and upregulated Nrf2 protein expression. In hepatic and pulmonary tissues, MCP downregulated the inflammatory signaling pathway, Gal-3/TLR-4/NF-κB/TNF-α. MCP pretreatment decreased TGF-β, collagen content, and cleaved caspase-3 levels. MCP enhanced the cytotoxicity of MTX in Nalm6 and JEG3 and did not interfere with its cytotoxicity in the MCF7 cell lines. MCP attenuated MTX-induced liver and lung toxicity through antioxidant, anti-fibrotic, anti-inflammatory, and anti-apoptotic influences, as demonstrated by the improved histopathological changes induced by MTX in pulmonary and hepatic tissues. Moreover, it increased MTX cytotoxicity in different human cell lines.

We previously demonstrated that the chronic consumption of a high-fat diet (HFD) promotes lung and liver metastases of 4T1 mammary carcinoma cells in obesity-resistant BALB/c mice. To examine early transcriptional responses to tumour progression in the liver and lungs of HFD-fed mice, 4-week-old female BALB/c mice were divided into four groups: sham-injected, control diet (CD)-fed; sham-injected, HFD-fed (SH); 4T1 cell-injected, CD-fed (TC); 4T1 cell-injected, HFD-fed (TH). Following 16 weeks of either a CD or HFD, 4T1 cells were injected into the mammary fat pads of mice in the TC and TH groups and all mice were continuously fed identical diets. At 14 d post-injection, RNA was isolated from hepatic and pulmonary tissues for microarray analysis of mRNA expression. Functional annotation and core network analyses were conducted for the TH/SH Unique gene set. Inflammation in hepatic tissues and cell mitosis in pulmonary tissues were the most significant biological functions in the TH/SH Unique gene set. The biological core networks of the hepatic TH/SH Unique gene set were characterised as those genes involved in the activation of acute inflammatory responses (Orm1, Lbp, Hp and Cfb), disordered lipid metabolism and deregulated cell cycle progression. Networks of the pulmonary Unique gene set displayed the deregulation of cell cycle progression (Cdc20, Cdk1 and Bub1b). These HFD-influenced alterations may have led to favourable conditions for the formation of both pro-inflammatory and pro-mitotic microenvironments in the target organs that promote immune cell infiltration and differentiation, as well as the infiltration and proliferation of metastatic tumour cells.

Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response

This review addresses recent progress in our understanding of the role of regulatory T (Treg) cells in enforcing immune tolerance and tissue homeostasis in the lung at steady state and in directing the immune response in asthmatic lung inflammation. Regulatory T cells regulate the innate and adaptive immune responses at steady state to enforce immune tolerance in lung tissues at steady state and their control of the allergic inflammatory responses induced by allergens. This regulatory function can break down in the context of chronic asthmatic airway inflammation such that the lung tissue Treg cells become skewed towards a pathogenic phenotype that aggravates and perpetuates disease. Subversion of lung tissue Treg cell function involves their upregulation of Notch4 expression, which in turn acts to amplify T helper type 2 and type 17 and innate lymphoid cell type 2 responses in the airways. A dual role for Treg cells has emerged both as immune regulators but also a potential disease effectors in asthma, with implications for disease therapy.

Periodontal disease is a complex, multifactorial condition characterized by chronic inflammation and progressive destruction of the tooth-supporting structures. Among its various forms, early-onset periodontitis is particularly aggressive and often associated with genetic predispositions. Genetic and epigenetic factors play pivotal roles in shaping host susceptibility to this disease by influencing immune responses, inflammatory regulation, and tissue homeostasis. Single-nucleotide polymorphisms (SNPs) in genes encoding cytokines, such as interleukin-1β and tumor necrosis factor-alpha, are linked to heightened inflammatory responses, amplifying tissue damage and accelerating disease progression. Additionally, polymorphisms in genes like TLR2 and TLR4 impair microbial recognition, promoting chronic inflammation and dysbiosis. Epigenetic modifications, including DNA methylation and histone acetylation, further modulate gene expression, contributing to the dynamic interplay between genetic predispositions and environmental factors like smoking or poor oral hygiene. Emerging research has also highlighted genetic markers such as human leukocyte antigen (HLA) alleles and matrix metalloproteinase (MMP) variants as predictors of disease severity and therapeutic outcomes. These insights have driven the development of targeted therapies, including inhibitors of pro-inflammatory mediators, MMP inhibitors, and potential miRNA-based interventions. High-throughput technologies, such as genome-wide association studies (GWAS), have expanded the understanding of genetic pathways involved in periodontal disease. These advances enable earlier disease detection and personalized treatment strategies, offering the potential to mitigate progression and reduce the burden of severe periodontitis. The integration of genetic and epigenetic research into clinical practice marks a significant step toward precision medicine, providing a framework for tailored prevention and therapeutic interventions aimed at improving patient outcomes. Future research must continue to explore these genetic mechanisms to uncover novel biomarkers and refine targeted treatment approaches for periodontal disease.

Background/aimPreterm births cause fetuses to be born without completing the development of their organs. Due to this undesirable situation, it is the pulmonary tissue which has to be most exposed to harmful effects of extrauterine environment. Early disappearance of the prophylactic and constructive effects of amniotic fluid (AF) on developing tissues, such as pulmonary tissue, facilitates the formation of pulmonary morbidities resulting from oxygen. Setting out from this knowledge, we wanted, in addition to assessing the beneficent effects of AF on pulmonary tissue, to study the importance of AF in morbidities of this tissue thought to originate from oxygen.Materials and methodsIn this experimental study, while the study group was made up of the fetuses of pregnant rats exposed to hyperbaric oxygen, (hyperoxic pregnant rat fetuses-HPRF), the control group was formed of the fetuses of the rats pregnant in the usual room setting (normoxic pregnant rat fetuses-NPRF). The pulmonary and hepatic tissues taken from the fetuses of these pregnant rats on the 21st day of their pregnancy were compared biochemically and histologically. For biochemical assessment, total glutathione (tGSH), catalase (CAT), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) values and for histopathological assessment, apoptosis, alveolar wall count (AWC), vena centralis count (VCC) were included.ResultsStatistical significance was found in the pulmonary tissue values of tGSH on behalf of NPRF, and MDA on behalf of HPRF (p < 0.05). In liver tissue, statistical significance was detected in tGSH and CAT values in favor of NPRF and in MDA, and TNF-α values in favor of HPRF (p < 0.05).ConclusionOur study has demonstrated that AF protects the pulmonary tissue from the harmful effects of oxygen in the intrauterine period. In addition, our data have suggested that the pulmonary tissue’s being deprived of the useful effects of AF owing to premature birth may be an important trigger in the occurrence of the pulmonary morbidities thought to result from oxygen.

Interventional study. To analyze the histologic effects of high-dose human equivalent methylprednisolone on the pulmonary, cardiac, intestinal, renal, hepatic, and splenic tissues in a spinal cord injury rat model. There are numerous investigations of various medical interventions for the treatment of acute spinal cord trauma. Currently, the only generally accepted medical intervention in an acute spinal cord trauma is the intravenous administration of high doses of methylprednisolone. Although it has been nearly 2 decades since the first National Acute Spinal Cord Injury Study investigated the role high-dose steroids might play in the treatment of acute spinal cord trauma, controversy still exists regarding the efficacy of this treatment. To our knowledge, no study has examined the role of high-dose methylprednisolone in organ systems other than the spinal cord in an acute spinal cord injury model at the histologic level. This study attempts to characterize end organ histologic response to human dose equivalent (HDE) intravenous methylprednisolone administration in a rodent model of acute spinal cord injury. A total of 48 Sprague-Dawley rats were divided equally into control and experimental groups. Each group was subdivided into 6 sets of 4 animals each, according to intervals after injury. Groups 1-6 consisted of animals euthanized at 0, 4, 8, 16, 24, and 48 hours after spinal cord injury. Paraplegia after lower thoracic laminectomy was achieved using a standardized Allen weight drop technique. Within 1 hour of injury, experimental animals were treated with HDE methylprednisolone, infused for 23 hours continuously. Liver, kidney, lung, intestine, spleen, and heart were harvested at variable intervals after injury and prepared for histologic examination. These slides were analyzed with microscopic staining techniques and compared in a blinded manner by a qualified pathologist. Of all the end organs analyzed, the spleens were most affected. Lymphocytic depletion was seen in as little as 4 hours after methylprednisolone infusion and continued until 48 hours. Pulmonary tissues variably showed interstitial congestion and eosinophilic alveolar collections. Intestinal mucosal tissues showed edema and autolyzed mucosa from 16 hours onwards. Cardiac, kidney, and hepatic tissue did not differ significantly from controls. Histologically, HDE methylprednisolone caused significant splenic lymphocytic depletion changes in as little as 4 hours. This trend of end organ lymphocytopenia continued to progress until 48 hours. Pulmonary eosinophilic infiltrates were seen from 8 until 24 hours. Intestinal mucosal edema and necrosis were seen in samples at 16 hours throughout 48 hours. This study was designed to evaluate end organ changes seen in an animal model of an acute spinal cord injury treated with HDE methylprednisolone. Study animals were infused with HDE methylprednisolone given according to the National Acute Spinal Cord Injury Study II protocol. The kidney, lung, cardiac, intestinal, splenic, and hepatic tissues from the aforementioned animals were then sectioned and analyzed using histologic staining techniques by a qualified pathologist.

Multiple Pathogenic Roles of Microvasculature in Inflammatory Bowel Disease: A Jack of All Trades