All implanted materials inevitably trigger an acute inflammatory response. The long-term outcome, however, is dependent on the trajectory of this response. This study investigates the effects of aging on the immune response to two commercially available biomaterials. Extracellular matrix-based urinary bladder matrix (UBM) and synthetic polypropylene mesh (PPM) were implanted in young (4 months) and aged (18 months) C57BL/6J mice. Overall, PPM led to a sustained inflammatory response regardless of the age of the mice. In contrast, UBM induced an initial inflammatory response that matured into a pro-regenerative/remodeling response with time, though aged mice exhibited a delayed resolution of inflammation. The PPM-induced response was predominantly pro-inflammatory with consistently higher M1-like macrophage phenotype, whereas the response to UBM was characterized by an anti-inflammatory M2-like phenotype, especially in young mice. RNA sequencing revealed marked age-related differences in gene transcription. At day 7 post-implantation, the young mice with UBM showed a robust upregulation of both pro- and anti-inflammatory pathways as compared to young mice implanted with PPM, however, by day 14, the gene expression profile transitioned into an anti-inflammatory profile. Intriguingly, in aged mice, the response to UBM was distinct with consistent downregulation of inflammatory genes compared to PPM, while the response to PPM in both young and aged animals was largely consistent. Upstream analysis identified cytokines as key drivers of the host response, with IL-4 and IL-13 in young mice, and TNF-α and IL-1β driving chronic inflammation in aged mice. These findings highlight the importance of host age in biomaterial outcome, and the potential of ECM-based materials to mount a favorable response even in the presence of age-related immune dysregulation.

Monocytes are innate immune cells that drive the chronicity of various inflammatory diseases. Monocyte migration to inflamed tissues involves multiple steps of interaction with the vascular endothelium and the extracellular matrix (ECM), a process mediated through conformational transitions in cell surface integrins. We previously described motile sperm domain-containing protein 2 (MOSPD2) as a surface protein expressed on myeloid cells that is essential for the migration of monocytes and a key regulator of inflammation. Investigating MOSPD2's mechanism of action, we assessed whether it plays a role in regulating integrin activation and monocyte adhesion. Data show that silencing of MOSPD2 expression in the THP-1 monocytic cell line significantly increased cell adhesion to various ECM molecules. Employing IW-601, a humanized anti-human MOSDP2 monoclonal antibody, on primary human monocytes increased adhesion to ECM molecules as well as to adhesion molecules. At the molecular level, silencing of MOSPD2 or blocking MOSPD2 using IW-601 led to a transition in integrin αLβ2 (CD11a/CD18, LFA-1) conformation into an active high-affinity binding form and to the induction of adhesion-associated signaling pathways. Co-immunoprecipitation experiments showed that MOSPD2 binds integrin-β2 (CD18), but not integrin-β1 (CD29). Our results reveal a novel mechanism controlling monocyte migration, in which MOSPD2 acts as an adhesion checkpoint that governs the balance between monocyte adhesion and release. By demonstrating the inhibitory effect of IW-601 on the migration of primary monocytes isolated from patients with chronic inflammatory diseases, we provide proof of concept for translating MOSPD2's mechanism into a potential treatment for inflammatory diseases, further supported by in vivo data in models of RA and IBD.

Ulcerative colitis (UC) involves chronic, complex pathology of the intestinal mucosa. Current treatments are limited in efficacy and associated with adverse effects, highlighting the urgent need for improved therapeutic options. Lentinan (LNT), a polysaccharide drug commonly used in clinical immune modulation therapies, shows potential for UC treatment, though its specific targets and mechanisms remain unclear. In this study, LNT administration effectively mitigated DSS-induced colitis in mice, enhanced mucosal barrier function and antimicrobial defense. Specifically, LNT modulated the balance between tissue-resident and infiltrating macrophages, thereby improving pathogen clearance and enhancing the immunological barrier. Notably, we identified a novel effect of LNT in regulating the macrophage Dectin-1-ILC3 axis to increase IL-22 secretion. This led to the modulation of epithelial O-glycan fucosylation, antimicrobial peptides, and epithelial stem cells, thereby strengthening antimicrobial defenses and the physicochemical barrier. Neutralization with anti-IL-22 antibodies diminished the therapeutic effect of LNT in UC, underscoring the critical role of IL-22 in LNT-mediated treatment. Overall, this study highlights the potential of LNT as a novel therapeutic agent for UC, offering new insights into its molecular mechanisms and clinical application.

Peritoneal macrophages, comprising large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs), play a vital role in maintaining immune defenses during inflammation. However, the molecular mechanisms governing their responses, particularly the impact of retinoic acid (RA), remain poorly understood. This study aims to elucidate the role of RA in modulating macrophage function, distribution, and immune responses during bacterial infections.

A murine model of peritonitis was established using Escherichia coli expressing a tdTomato fluorescence marker. The effects of RA on macrophage phagocytic capacity, population dynamics, and transcriptomic profiles were assessed using immunofluorescence, flow cytometry, RNA sequencing, and quantitative PCR. Additionally, RA-loaded ZIF-8 nanoparticles were employed to investigate the sustained effects of RA delivery.

RA significantly enhanced macrophage phagocytic activity, delayed functional decline, and promoted the recruitment of SPMs in the peritoneal cavity. Transcriptomic analysis revealed upregulation of leukocyte migration and cell adhesion pathways in RA-treated SPMs. RA treatment also induced distinct gene expression profiles in macrophage subpopulations, reflecting its role in immune modulation. Notably, RA-loaded ZIF-8 nanoparticles prolonged RA retention within macrophages, sustaining its effects.

RA enhances antibacterial defense by modulating macrophage activity, providing new insights into immune regulation. These findings underscore the therapeutic potential of RA and its nanoparticle formulations in managing bacterial infections and inflammation.

Myeloid-derived suppressor cells (MDSCs) regulate immune responses in many pathological conditions, one of which is inflammatory bowel disease (IBD), an incurable chronic disorder of the digestive tract and beyond. The pathophysiology of IBD remains unclear, likely involving aberrant innate and adaptive immunity. Studies have reported altered population of MDSCs in patients with IBD. However, their distribution varies among patients and different preclinical models of IBD. The expansion and activation of MDSCs are likely driven by various stimuli during intestinal inflammation, but the in-depth mechanisms remain poorly understood. The role of MDSCs in the pathogenesis of IBD appears to be paradoxical. In addition to intestinal inflammation, suppressive MDSCs may promote colitis-to-colon cancer transition. In this Review, we summarize recent progresses on the features, activation, and roles of MDSCs in the development of IBD and IBD-associated colon cancer.

Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.

Mouse resident peritoneal macrophages, called large cavity macrophages (LCM), arise from embryonic progenitors that proliferate as mature, CD73+Gata6+ tissue-specialized macrophages. After injury from irradiation or inflammation, monocytes are thought to replenish CD73+Gata6+ LCMs through a CD73-LYVE1+ LCM intermediate. Here, we show that CD73-LYVE1+ LCMs indeed yield Gata6+CD73+ LCMs through integrin-mediated interactions with mesothelial surfaces. CD73-LYVE1+ LCM repopulation of the peritoneum was reliant upon and quantitatively proportional to recruited monocytes. Unexpectedly, fate mapping indicated that only ~10% of Gata6-dependent LCMs that repopulated the peritoneum after injury depended on the LYVE1+ LCM stage. Further supporting nonoverlapping lifecycles of CD73-LYVE1+ and CD73+Gata6+ LCMs, in mice bearing a paucity of monocytes, Gata6+CD73+ LCMs rebounded after ablative irradiation substantially more efficiently than their presumed LYVE1+ or CD73- LCM upstream precursors. Thus, after inflammatory insult, two temporally parallel pathways, each generating distinct differentiation intermediates with varying dependencies on monocytes, contribute to the replenish hment of Gata6+ resident peritoneal macrophages.

Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.

Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood-brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, which increases the incidence of colorectal cancer (CRC). In the pathophysiology of IBD, ubiquitination/deubiquitination plays a critical regulatory function. Josephin domain containing 2 (JOSD2), a deubiquitinating enzyme, controls cell proliferation and carcinogenesis. However, its role in IBD remains unknown. Colitis mice model developed by dextran sodium sulfate (DSS) or colon tissues from individuals with ulcerative colitis and Crohn's disease showed a significant upregulation of JOSD2 expression in the macrophages. JOSD2 deficiency exacerbated the phenotypes of DSS-induced colitis by enhancing colon inflammation. DSS-challenged mice with myeloid-specific JOSD2 deletion developed severe colitis after bone marrow transplantation. Mechanistically, JOSD2 binds to the C-terminal of inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) and preferentially cleaves K63-linked polyubiquitin chains at the K134 site, suppressing IMPDH2 activity and preventing activation of nuclear factor kappa B (NF-κB) and inflammation in macrophages. It was also shown that JOSD2 knockout significantly exacerbated increased azoxymethane (AOM)/DSS-induced CRC, and AAV6-mediated JOSD2 overexpression in macrophages prevented the development of colitis in mice. These outcomes reveal a novel role for JOSD2 in colitis through deubiquitinating IMPDH2, suggesting that targeting JOSD2 is a potential strategy for treating IBD.

Macrophages are members of the human innate immune system, and the majority reside in the liver. In recent years, they have been recognized as essential players in the maintenance of liver and intestinal homeostasis as well as key guardians of their respective immune systems, and they are increasingly being recognized as such. Paradoxically, they are also likely involved in chronic pathologies of the gastrointestinal tract and potentially in the alteration of the gut-liver axis in alcohol use disorder (AUD) and alcohol-associated liver disease (ALD). To date, the causal relationship between macrophages, the pathogenesis of ALD, and the immune dysregulation of the gut remains unclear. In this review, we will discuss our current understanding of the heterogeneity of intestinal and hepatic macrophages, their ontogeny, the potential factors that regulate their origin, and the evidence of how they are associated with the manifestation of chronic inflammation. We will also illustrate how the micro-environment of the intestine shapes the phenotypes and functionality of the macrophage compartment in both the intestines and liver and how they change during chronic alcohol abuse. Finally, we highlight the obstacles to current research and the prospects for this field.

Under physiological conditions, the inflammatory response acts as a biological defense against tissue damage or infection, and is rapidly resolved once the infection is cleared. However, chronic inflammatory diseases, including inflammatory bowel disease (IBD), have become increasingly widespread in the last decades, placing a burden on the quality of life of affected people and on healthcare systems worldwide. Available drug therapies are often ineffective due to the chronic nature of these diseases, and prolonged administration of drugs can result in severe side effects for the patient or a lack of efficacy. In addition, there is the growing problem of bacterial resistance to synthetic antibiotics. Together, these factors have led to a strong research focus on the discovery of natural products capable of treating IBD. Recently, there has been a growing interest in compounds derived from marine sources, mainly algae, due to their bioactive secondary metabolites with anti-inflammatory properties well known in the literature. Based on this evidence, this review aimed to evaluate the anti-inflammatory potential of algae-derived biomolecules in IBD. In particular, interesting species from green algae (e.g., Chlorella vulgaris and Ulva pertusa), brown algae (e.g., Macrocystis pyrifera and Ecklonia cava) and red algae (e.g., Porphyra tenera and Grateloupia turuturu) are included in this review due to their proven anti-inflammatory properties. For this purpose, an extensive literature search was conducted using several databases. The results suggest that both macroalgae and microalgae have remarkable potential for IBD therapy due to the anti-inflammatory and antioxidant activities of their bioactive compounds. However, while the preclinical evidence is encouraging, further and long-term clinical studies are needed to better understand their mechanisms of action in order to determine the true efficacy of marine algae in the treatment of IBD.

The intestinal epithelium is a rapidly self-renewing tissue; the rapid turnover prevents the invasion of pathogens and harmful components from the intestinal lumen, preventing inflammation and infectious diseases. Intestinal epithelial barrier function depends on the epithelial cell proliferation and junctions, as well as the state of the immune system in the lamina propria. Polyamines, particularly putrescine, spermidine, and spermine, are essential for many cell functions and play a crucial role in mammalian cellular homeostasis, such as that of cell growth, proliferation, differentiation, and maintenance, through multiple biological processes, including translation, transcription, and autophagy. Although the vital role of polyamines in normal intestinal epithelial cell growth and barrier function has been known since the 1980s, recent studies have provided new insights into this topic at the molecular level, such as eukaryotic initiation factor-5A hypusination and autophagy, with rapid advances in polyamine biology in normal cells using biological technologies. This review summarizes recent advances in our understanding of the role of polyamines in regulating normal, non-cancerous, intestinal epithelial barrier function, with a particular focus on intestinal epithelial renewal, cell junctions, and immune cell differentiation in the lamina propria.

Intestinal epithelial cells (IECs) and innate immune cells in the gastrointestinal tract (GIT) of chickens play crucial roles in pathogens defense and maintaining gut health. However, their effectiveness influenced with their developmental and functional stages during pre and post hatch periods of chick. During embryonic development, differentiation and migration of these innate immune systems are tightly regulated by diverse cellular and molecular factors. The maturation and functionality of IECs are histologically evident starting embryonic day (ED) 14. Moreover, the innate immun cells, such as dendritic cells (DCs), macrophages, natural killer (NK) cells, and gamma-delta (γδ) T cells have showed developmental expression varation, while most identified by the 3rd days of incubation and capable of responsing to their cognate ligands of pathogens by ED 17, it may not efficient during posthatch period. In modern poultry production, in ovo feeding of bioactive substances is a topic of interest to maximize the protection capability of hatched chicks by enhancing improvement on the development of innate immune systems. However, their actions and effects on each distinct innate immune involved response are inconsistent and not clearly understood. Thus, summarizing the ontogeny and function of IECs, innate immunity systems, and interaction mechanisms of in ovo feeding of bioactive substances could provide baseline information for designing targeted in ovo feeding interventions to modulate cell waise specific innate immune systems.

The potential for mitigating intestinal inflammation through the gut-bone axis in the treatment of osteoporosis is significant. While various gut-derived postbiotics or bacterial metabolites have been created as dietary supplements to prevent or reverse bone loss, their efficacy and safety still need improvement. Herein, a colon-targeted drug delivery system is developed using surface engineering of polyvinyl butyrate nanoparticles by shellac resin to achieve sustained release of postbiotics butyric acid at the colorectal site. These engineered postbiotics nanoparticles can effectively suppress macrophage inflammatory activation, modulate the redox balance, and regulate the composition of the gut microbiota, thereby restoring epithelial barriers, inhibiting bacterial invasion, and down-regulating pro-inflammatory responses. As a result, the remission of systemic inflammation is accompanied by a rebalancing of osteoblast and osteoclast activity, alleviating inflammatory bowel disease-related and post-menopausal bone loss. Specifically, the treatment of engineered postbiotics nanoparticles can also improve the quality and quantity of bone with restoration of deteriorative mechanical properties, which indicating a therapeutic potential on fracture prevention. This study provides valuable insights into the gut-bone axis and establishes a promising and safe therapeutic strategy for osteoporosis.

Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are the leading cause of mortality among patients with IPF. There is still a lack of effective treatments for AE-IPF, resulting in a hospitalization mortality rate as high as 70%-80%. To reveal the complicated mechanism of AE-IPF, more attention has been paid to its disturbed immune environment, as patients with IPF exhibit deficiencies in pathogen defense due to local immune dysregulation. During the development of AE-IPF, the classical stimulatory signals in adaptive immunity are inhibited, while the nonclassical immune reactions (Th17) are activated, attracting numerous neutrophils and monocytes to lung tissues. However, there is limited information about the specific changes in the immune response of AE-IPF. We summarized the immune mechanisms of AE-IPF in this review.

Despite significant advances in biologic and small molecule treatments and the emergence of combination therapies to treat inflammatory bowel diseases (IBD) a large unmet need remains to control intestinal inflammation. New approaches targeting several pathways simultaneously with a favorable safety profile and agents that trigger anti-inflammatory pathways to drive durable resolution of inflammation are needed. This article discusses novel cellular immunotherapies and immune cell depleting therapies in IBD, including CAR-T cell approaches, Tr1 and T regulatory (Treg) cells and cell depleting antibodies such as rosnilimab. These novel approaches have the potential to overcome current therapeutic limitations in the treatment of IBD.

The past 15 years have witnessed a leap in understanding the life cycle, gene expression profiles, origins and functions of mouse macrophages in many tissues, including macrophages of the artery wall and heart that have critical roles in cardiovascular health. Here, we review the phenotypical and functional diversity of macrophage populations in multiple organs and discuss the roles that proliferation, survival, and recruitment and replenishment from monocytes have in maintaining macrophages in homeostasis and inflammatory states such as atherosclerosis and myocardial infarction. We also introduce emerging data that better characterize the life cycle and phenotypic profiles of human macrophages. We discuss the similarities and differences between murine and human macrophages, raising the possibility that tissue-resident macrophages in humans may rely more on bone marrow-derived monocytes than in mouse.

Aggregating immune cells within perivascular niches (PVN) can regulate tissue immunity in infection, autoimmunity and cancer. How cells are assembled at PVNs and the activation signals imparted within remain unclear. Here, we integrate dynamic time-resolved in vivo imaging with a novel spatially-resolved platform for microanatomical interrogation of transcriptome, immune phenotype and inflammatory mediators in skin PVNs. We uncover a complex positive-feedback loop within CXCL10 + PVNs that regulates myeloid and Th1 cell positioning for exchange of critical signals for Th1 activation. Th1 cells spend ∼24h in the PVN, receiving initial peripheral activation signals, before redeploying to the inflamed dermal parenchyma. Niche-enriched, CCR2-dependent myeloid cells were critical for Th1 IFNγ-production. In turn, PVN instructional signals enabled Th1s to orchestrate PVN assembly by CXCR2-dependent intra-tissue myeloid cell aggregation. The results reveal a critical tissue organizing role for Th1s, gained rapidly on tissue entry, that could be exploited to boost regional immunity.

Perivascular niche (PVN): myeloid hubs in inflamed mouse and healthy human skinTh1 cells enter, get activated, and leave the PVN within first 24h of tissue entryAntigen-specific signals in the PVN promote the tissue organizing functions of Th1sTh1 cells assemble the PVN via CXCR2-dependent myeloid cell aggregation.

Mesenchymal stem cells (MSCs) have shown potential in treating immune-mediated diseases due to their immunomodulatory properties, which can be enhanced by priming with inflammatory cytokines like interferon-gamma (IFN-γ). This study evaluates the therapeutic effects of IFN-γ-primed canine adipose tissue-derived MSCs (AMSCs) in a mouse model of inflammatory bowel disease (IBD). Canine AMSCs were primed with 50 ng/mL recombinant canine IFN-γ for 48 h, and the effects were compared to those seen in naïve (unprimed) AMSCs. IBD was induced in mice using dextran sodium sulfate (DSS), and AMSCs were injected intraperitoneally on days 1 and 3. The mice treated with IFN-γ-primed AMSCs showed improved clinical outcomes, including a reduced disease activity index (DAI), less body weight loss, and longer colon length compared to the mice treated with naïve AMSCs. A histological analysis revealed less damage to the intestinal structures and reduced inflammatory cell infiltration. IFN-γ priming led to a shift in the immune cell balance in the gut, decreasing pro-inflammatory macrophages (Ly6Chi) and increasing anti-inflammatory macrophages (Ly6Clo/MHC-IIhi). This was associated with the reduced expression of inflammatory cytokine genes (Il-1β, Il-6, and Il-18) and increased expression of the intestinal stem cell marker Lgr5. These findings suggest that IFN-γ-primed AMSCs offer enhanced therapeutic potential for treating CE in veterinary medicine.

Anti-integrin αvβ6 autoantibodies (anti-αvβ6) are found in more than 50% of individuals with ulcerative colitis (UC). We aimed to determine the prevalence of anti-αvβ6 in patients with primary sclerosing cholangitis (PSC) and their association with liver disease severity.

Four cohorts of pre-liver transplant patients with PSC were recruited. Patients with inflammatory bowel disease (IBD) and healthy controls (HCs) served as comparators. Total IgG and anti-αvβ6 levels were measured using enzyme-linked immunosorbent assay. Olink inflammation panel was run on a subset of samples. Multivariable linear regression analysis was performed to assess the association between anti-αvβ6 and indices of liver disease severity.

A total of 137 patients with PSC (including 76 with PSC-UC, 33 with PSC-Crohn's disease (CD), and 28 with PSC alone) and 160 controls (including 91 with IBD and 69 HCs) were enrolled. Anti-αvβ6 levels were significantly higher in PSC-UC and PSC-CD compared with PSC alone (P < .0001 and P < .003) and HCs (P < .0001 and P < .0001). However, anti-αvβ6 levels in PSC alone were not increased compared with HCs. In patients with PSC-IBD, anti-αvβ6 levels correlated with markers of liver disease severity, including alkaline phosphatase level (r = 0.32; P = .004), the revised Mayo PSC risk score (r = 0.25; P = .02), and liver stiffness measurement (r = 0.43; P = .008) after adjusting for age, gender, race/ethnicity, and IBD subtype. Additionally, anti-αvβ6 levels were associated with markers of systemic inflammation and tissue remodeling.

Anti-αvβ6 autoantibodies identify a subset of patients with PSC with concomitant IBD.

Studying viral infections necessitates well-designed cell culture models to deepen our understanding of diseases and develop effective treatments. In this study, we present a readily available ex vivo 3D co-culture model replicating the human intestinal mucosa. The model combines fully differentiated human intestinal epithelium (HIE) with human monocyte-derived macrophages (hMDMs) and faithfully mirrors the in vivo structural and organizational properties of intestinal mucosal tissues. Specifically, it mimics the lamina propria, basement membrane, and the air-exposed epithelial layer, enabling the pioneering observation of macrophage migration through the tissue to the site of viral infection. In this study, we applied the HIE-hMDMs model for the first time in viral infection studies, infecting the model with two globally significant viruses: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human norovirus GII.4. The results demonstrate the model's capability to support the replication of both viruses and show the antiviral role of macrophages, determined by their migration to the infection site and subsequent direct contact with infected epithelial cells. In addition, we evaluated the production of cytokines and chemokines in the intestinal niche, observing an increased interleukin-8 production during infection. A parallel comparison using a classical in vitro cell line model comprising Caco-2 and THP-1 cells for SARS-CoV-2 experiments confirmed the utility of the HIE-hMDMs model in viral infection studies. Our data show that the ex vivo tissue models hold important implications for advances in virology research.IMPORTANCEThe fabrication of intricate ex vivo tissue models holds important implications for advances in virology research. The co-culture model presented here provides distinct spatial and functional attributes not found in simplified models, enabling the evaluation of macrophage dynamics under severe acute respiratory syndrome coronavirus 2 and human norovirus (HuNoV) infections in the intestine. Moreover, these models, comprised solely of primary cells, facilitate the study of difficult-to-replicate viruses such as HuNoV, which cannot be studied in cell line models, and offer the opportunity for personalized treatment evaluations using patient cells. Similar co-cultures have been established for the study of bacterial infections and different characteristics of the intestinal tissue. However, to the best of our knowledge, a similar intestinal model for the study of viral infections has not been published before.

Colorectal cancer (CRC) resulting from chronic inflammation is a crucial issue in patients with inflammatory bowel disease (IBD). Although many reports established that intestinal resident CX3CR1high macrophages play an essential role in suppressing intestinal inflammation, their function in colitis-related CRC remains unclear. In this study, we found that colonic CX3CR1high macrophages, which were positive for MHC-II, F4/80 and CD319, promoted colitis-associated CRC. They highly expressed Col1a1, Tgfb, II10, and II4, and were considered to be fibrocytes with an immunosuppressive M2-like phenotype. CX3CR1 deficiency led to reductions in the absolute numbers of CX3CR1high fibrocytes through increased apoptosis, thereby preventing the development of colitis-associated CRC. We next focused statins as drugs targeting CX3CR1high fibrocytes. Statins have been actively discussed for patients with IBD and reported to suppress the CX3CL1/CX3CR1 axis. Statin treatment after azoxymethane/dextran sulfate sodium-induced inflammation reduced CX3CR1high fibrocyte counts and suppressed colitis-associated CRC. Therefore, CX3CR1high fibrocytes represent a potential target for carcinogenesis-preventing therapy, and statins could be safe therapeutic candidates for IBD.

Dendritic cells (DCs) play a crucial role in orchestrating immune responses, particularly in promoting IFNγ-producing-CD8 cytotoxic T lymphocytes (CTLs) and IFNγ-producing-CD4 T helper 1 (Th1) cells, which are essential for defending against viral infections. Additionally, the nuclear envelope protein lamin A/C has been implicated in T cell immunity. Nevertheless, the intricate interplay between innate and adaptive immunity in response to viral infections, particularly the role of lamin A/C in DC functions within this context, remains poorly understood. In this study, we demonstrate that mice lacking lamin A/C in myeloid LysM promoter-expressing cells exhibit a reduced capacity to induce Th1 and CD8 CTL responses, leading to impaired clearance of acute primary Vaccinia virus (VACV) infection. Remarkably, in vitro-generated granulocyte macrophage colony-stimulating factor bone marrow-derived DCs (GM-CSF BMDCs) show high levels of lamin A/C. Lamin A/C absence on GM-CSF BMDCs does not affect the expression of costimulatory molecules on the cell membrane but it reduces the cellular ability to form immunological synapses with naïve CD4 T cells. Lamin A/C deletion induces alterations in NFκB nuclear localization, thereby influencing NF-κB-dependent transcription. Furthermore, lamin A/C ablation modifies the gene accessibility of BMDCs, predisposing these cells to mount a less effective antiviral response upon TLR stimulation. This study highlights the critical role of DCs in interacting with CD4 T cells during antiviral responses and proposes some mechanisms through which lamin A/C may modulate DC function via gene accessibility and transcriptional regulation.

Unlike sessile macrophages that occupy specialized tissue niches, non-classical monocytes (NCMs)-circulating phagocytes that patrol and cleanse the luminal surface of the vascular tree-are characterized by constant movement. Here, we examined the nature of the NCM's nurturing niche. Expression of the growth factor CSF1 on endothelial cells was required for survival of NCMs in the bloodstream. Lack of endothelial-derived CSF1 did not affect blood CSF1 concentration, suggesting that NCMs rely on scavenging CSF1 present on endothelial cells. Deletion of the transmembrane chemokine and adhesion factor CX3CL1 on endothelial cells impaired NCM survival. Mechanistically, endothelial-derived CX3CL1 and integrin subunit alpha L (ITGAL) facilitated the uptake of CSF1 by NCMs. CSF1 was produced by all tissular endothelial cells, and deletion of Csf1 in all endothelial cells except bone marrow sinusoids impaired NCM survival, arguing for a model where the full vascular tree acts as a niche for NCMs and where survival and patrolling function are connected.

This comprehensive review undertakes a multidisciplinary exploration of the gut-lung axis, from the foundational aspects of anatomy, embryology, and histology, through the functional dynamics of pathophysiology, to implications for clinical science. The gut-lung axis, a bidirectional communication pathway, is central to understanding the interconnectedness of the gastrointestinal- and respiratory systems, both of which share embryological origins and engage in a continuous immunological crosstalk to maintain homeostasis and defend against external noxa. An essential component of this axis is the mucosa-associated lymphoid tissue system (MALT), which orchestrates immune responses across these distant sites. The review delves into the role of the gut microbiome in modulating these interactions, highlighting how microbial dysbiosis and increased gut permeability ("leaky gut") can precipitate systemic inflammation and exacerbate respiratory conditions. Moreover, we thoroughly present the implication of the axis in oncological practice, particularly in lung cancer development and response to cancer immunotherapies. Our work seeks not only to synthesize current knowledge across the spectrum of science related to the gut-lung axis but also to inspire future interdisciplinary research that bridges gaps between basic science and clinical application. Our ultimate goal was to underscore the importance of a holistic understanding of the gut-lung axis, advocating for an integrated approach to unravel its complexities in human health and disease.

Modulation of immune microenvironment is critical for inflammatory bowel disease (IBD) intervention. Epigallocatechin gallate (EGCG), as a natural low toxicity product, has shown promise in treating IBD. However, whether and how EGCG regulates the intestinal microenvironment is not fully understood. Here we report that EGCG lessens colitis by orchestrating Th1 polarization and self-amplification in a novel manner that required multilevel-regulated intestinal microecosystem. Mechanistically, EGCG activates GPR43 on IEC to inhibit Th1 polarization dependently of short chain fatty acid (SCFA)-producing gut microbiota. Inhibition of GPR43 activity weakens the protective effects of EGCG on colitis development. Moreover, we confirm that fecal SCFAs and/or intestinal GPR43 are limited in patients with colitis and are correlated with Th1 cell number. Taken together, our study reveals an intestinal microenvironment-dependent immunoregulatory effects of EGCG in treating IBD and provides insight into mechanisms of EGCG-based novel immunotherapeutic strategies for IBD.

Monocytes are a key component of the innate immune system. They undergo intricate developmental processes within the bone marrow, leading to diverse monocyte subsets in the circulation. In a state of healthy homeostasis, monocytes are continuously released into the bloodstream, destined to repopulate specific tissue-resident macrophage pools where they fulfil tissue-specific functions. However, under pathological conditions monocytes adopt various phenotypes to resolve inflammation and return to a healthy physiological state. This review explores the nuanced developmental pathways and functional roles that monocytes perform, shedding light on their significance in both physiological and pathological contexts.

Intestinal dysmotility syndromes have been epidemiologically associated with several antecedent bacterial and viral infections. To model this phenotype, we previously infected mice with the neurotropic flavivirus West Nile virus (WNV) and demonstrated intestinal transit defects. Here, we found that within 1 week of WNV infection, enteric neurons and glia became damaged, resulting in sustained reductions of neuronal cells and their networks of connecting fibers. Using cell-depleting antibodies, adoptive transfer experiments, and mice lacking specific immune cells or immune functions, we show that infiltrating WNV-specific CD4+ and CD8+ T cells damaged the enteric nervous system (ENS) and glia, which led to intestinal dysmotility; these T cells used multiple and redundant effector molecules including perforin and Fas ligand. In comparison, WNV-triggered ENS injury and intestinal dysmotility appeared to not require infiltrating monocytes, and damage may have been limited by resident muscularis macrophages. Overall, our experiments support a model in which antigen-specific T cell subsets and their effector molecules responding to WNV infection direct immune pathology against enteric neurons and supporting glia that results in intestinal dysmotility.

Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory bowel diseases with limited therapeutic outcomes, is characterized by immune disorders and intestinal barrier dysfunction. Currently, the most medications used to cure IBD in clinic just temporarily induce and maintain remission with poor response rates and limited outcomes. Therefore, it is urgently necessary to develop an appropriate therapeutic candidate with preferable efficacy and less adverse reaction for curing IBD.

Five groups of mice were utilized: control that received saline, DSS group (mice received 2.5% DSS or 4% DSS), KPV group (mice received KPV), FK506 group (mice received FK506) and NPs groups (mice received NPs). The effect of NP on the inflammatory factors of macrophage was evaluated using CCK-8, quantitative polymerase chain reaction (PCR), Elisa and Western blot (WB). Immunofluorescent staining revealed the targeting relationship between NP and Petp-1. Immunohistochemistry staining showed the effect of NP on tight junction proteins. Moreover, in vivo animal experiments confirmed that NPs reduced inflammatory levels in IBD.

After administering with NPs, mice with DSS-induced acute or chronic colitis exhibited significant improvement in body weight, colon length, and disease activity index, decreased the level of the factors associated with oxidative stress (MPO, NO and ROS) and the inflammatory cytokines (TNF-α, IL-1β and IL-6), which implied that NPs could ameliorate murine colitis effectively. Furthermore, treating by NPs revealed a notable reduction of the expressions of CD68 and CD3, restoring the expression levels of tight junction proteins (Claudin-5, Occludin-1, and ZO-1) were significantly restored, surpassing those observed in the KPV and FK506 groups. which indicated that NPs can reduce inflammation and enhance epithelial barrier integrity by decreasing the infiltration of macrophages and T-lymphocytes. Collectively, those results demonstrated the effectively therapeutic outcome after using NPs in both acute and chronic colitis, suggesting that the newly co-assembled of NPs can be as a potential therapeutic candidate for colitis.

Endometriosis is a chronic inflammatory disease that causes debilitating pelvic pain in women. Macrophages are considered to be key players in promoting disease progression, as abundant macrophages are present in ectopic lesions and elevated in the peritoneum. In the present study, we examined the role of GATA6+ peritoneal macrophages on endometriosis-associated hyperalgesia using mice with a specific myeloid deficiency of GATA6. Lesion induction induced the disappearance of TIM4hi MHCIIlo residential macrophages and the influx of increased Ly6C+ monocytes and TIM4lo MHCIIhi macrophages. The recruitment of MHCIIhi inflammatory macrophages was extensive in Mac Gata6 KO mice due to the severe disappearance of TIM4hi MHCIIlo residential macrophages. Ki67 expression confirmed GATA6-dependent proliferative ability, showing different proliferative phenotypes of TIM4+ residential macrophages in Gata6f/f and Mac Gata6 KO mice. Peritoneal proinflammatory cytokines were elevated after lesion induction. When cytokine levels were compared between Gata6f/f and Mac Gata6 KO mice, TNFα at day 21 in Gata6f/f mice was higher than in Mac Gata6 KO mice. Lesion induction increased both abdominal and hind paw sensitivities. Gata6f/f mice tended to show higher sensitivity in the abdomen after day 21. Elevated expression of TRPV1 and CGRP was observed in the dorsal root ganglia after ELL induction in Gata6f/f mice until days 21 and 42, respectively. These results support that peritoneal GATA6+ macrophages are involved in the recruitment and reprogramming of monocyte-derived macrophages. The extensive recruitment of monocyte-derived macrophages in Mac Gata6 KO mice might protect against inflammatory stimuli during the resolution phase, whereas GATA6 deficiency did not affect lesion initiation and establishment at the acute phase of inflammation. GATA6+ residential macrophages act to sustain local inflammation in the peritoneum and sensitivities in the neurons, reflecting endometriosis-associated hyperalgesia.

Monocytes and macrophages play an indispensable role in maintaining intestinal homeostasis and modulating mucosal immune responses in inflammatory bowel disease (IBD). Although numerous studies have described macrophage properties in IBD, the underlying mechanisms whereby the monocyte-macrophage lineage modulates intestinal homeostasis during gut inflammation remain elusive.

In this review, we decipher the cellular and molecular mechanisms governing the generation of intestinal mucosal macrophages and fill the knowledge gap in understanding the origin, maturation, classification, and functions of mucosal macrophages in intestinal niches, particularly the phagocytosis and bactericidal effects involved in the elimination of cell debris and pathogens. We delineate macrophage-mediated immunoregulation in the context of producing pro-inflammatory and anti-inflammatory cytokines, chemokines, toxic mediators, and macrophage extracellular traps (METs), and participating in the modulation of epithelial cell proliferation, angiogenesis, and fibrosis in the intestine and its accessory tissues. Moreover, we emphasize that the maturation of intestinal macrophages is arrested at immature stage during IBD, and the deficiency of MCPIP1 involves in the process via ATF3-AP1S2 signature. In addition, we confirmed the origin potential of IL-1B+ macrophages and defined C1QB+ macrophages as mature macrophages. The interaction crosstalk between the intestine and the mesentery has been described in this review, and the expression of mesentery-derived SAA2 is upregulated during IBD, which contributes to immunoregulation of macrophage. Moreover, we also highlight IBD-related susceptibility genes (e.g., RUNX3, IL21R, GTF2I, and LILRB3) associated with the maturation and functions of macrophage, which provide promising therapeutic opportunities for treating human IBD.

In summary, this review provides a comprehensive, comprehensive, in-depth and novel description of the characteristics and functions of macrophages in IBD, and highlights the important role of macrophages in the molecular and cellular process during IBD.

Monocyte recruitment in the lamina propria and inflammatory phenotype driven by the mucosal microenvironment is critical for the pathogenesis of inflammatory bowel disease. However, the stimuli responsible remain largely unknown. Recent works have focused on stromal cells, the main steady-state cellular component in tissue, as they produce pro-inflammatory chemokines that contribute to the treatment-resistant nature of IBD.

We studied the regulation of these processes by examining the communication patterns between stromal and myeloid cells in ileal Crohn's disease (CD) using a complete single-cell whole tissue sequencing analysis pipeline and in vitro experimentation in mesenchymal cells.

We report expansion of S4 stromal cells and monocyte-like inflammatory macrophages in the inflamed mucosa and describe interactions that may establish sustained local inflammation. These include expression of CCL2 by S1 fibroblasts to recruit and retain monocytes and macrophages in the mucosa, where they receive signals for proliferation, survival, and differentiation to inflammatory macrophages from S4 stromal cells through molecules such as MIF, IFNγ, and FN1. The overexpression of CCL2 in ileal CD and its stromal origin was further demonstrated in vitro by cultured mesenchymal cells and intestinal organoids in the context of an inflammatory milieu.

Our findings outline an extensive cross-talk between stromal and myeloid cells, which may contribute to the onset and progression of inflammation in ileal Crohn's disease. Understanding the mechanisms underlying monocyte recruitment and polarization, as well as the role of stromal cells in sustaining inflammation, can provide new avenues for developing targeted therapies to treat IBD.

Ulcerative colitis (UC) is associated with intestinal macrophage infiltration due to disruption of the mucosal barrier and bacterial invasion. Therefore, it is crucial to identify therapeutic agents capable of attenuating the macrophage-induced inflammatory response to preserve mucosal homeostasis and immune tolerance. The modified Zhenwu decoction (CDD-2103) is a novel herbal formulation developed based on the principles of Traditional Chinese medicine. To date, there are no clinically approved herbal formulations for UC with a well-known mechanism of action on macrophages.

The objective of this study was to systematically investigate the inhibitory effect of the active fraction of CDD-2103 in a mouse model of chronic colitis and delineate the mechanisms underlying its inhibitory action.

CDD-2103 was extracted into four fractions using organic solvents with increasing polarity. A chronic 49-day dextran sulfate sodium (DSS)-induced colitis mice model, closely resembling human clinical conditions, was used to examine the effect of CDD-2103 on chronic colitis. To confirm the effect of CDD-2103 on macrophages in this chronic colitis model, adoptive macrophage transfer and CCL2 supplementation were conducted. The mechanisms of action of CDD-2103 were further elucidated utilizing bone marrow-derived macrophages (BMDMs). Transcriptome analysis was conducted to gain insights into the underlying mechanism of action of CDD-2103 in BMDMs.

Our in vitro and in vivo findings demonstrated that the ethanol-enriched fraction of CDD-2103 exhibited significant anti-inflammatory effects, leading to the suppression of colitis severity. This effect was associated with diminished accumulation of colonic macrophages in the lamina propria of CDD-2103-intervened colitis mice. Specifically, CDD-2103 inhibited CCR2/L2-mediated proinflammatory macrophage infiltration into the colon without affecting macrophage proliferation. Mechanistically, CDD-2103 inhibited Fyn expression-mediated p38 MAPK activation and subsequently suppressed CCR2 expression in BMDMs.

Collectively, our study supports the potential use of CDD-2103 to limit macrophage infiltration, thereby reducing inflammation during UC treatment. CDD-2103 and the components in the ethanolic fraction are promising candidates for the development of novel drugs for UC management. Additionally, our study underscores Fyn-mediated CCR2 expression as a potential therapeutic target for the management of UC.

Lymph node stromal cells (LNSCs) are an often overlooked component of the immune system but play a crucial role in maintaining tissue homeostasis and orchestrating immune responses. Our understanding of the functions these cells serve in the context of bacterial infections remains limited. We previously showed that Listeria monocytogenes, a facultative intracellular foodborne bacterial pathogen, must replicate within an as-yet-unidentified cell type in the mesenteric lymph node (MLN) to spread systemically. Here, we show that L. monocytogenes could invade, escape from the vacuole, replicate exponentially, and induce a type I interferon response in the cytosol of 2 LNSC populations infected in vitro, fibroblastic reticular cells (FRCs) and blood endothelial cells (BECs). Infected FRCs and BECs also produced a significant chemokine and proinflammatory cytokine response after in vitro infection. Flow cytometric analysis confirmed that GFP+  L. monocytogenes were associated with a small percentage of MLN stromal cells in vivo following foodborne infection of mice. Using fluorescent microscopy, we showed that these cell-associated bacteria were intracellular L. monocytogenes and that the number of infected FRCs and BECs changed over the course of a 3-day infection in mice. Ex vivo culturing of these infected LNSC populations revealed viable, replicating bacteria that grew on agar plates. These results highlight the unexplored potential of FRCs and BECs to serve as suitable growth niches for L. monocytogenes during foodborne infection and to contribute to the proinflammatory environment within the MLN that promotes clearance of listeriosis.