Prior exposure to microenvironmental signals could fundamentally change the response of macrophages to subsequent stimuli. It is believed that T helper-2 (Th2)-cell-type cytokine interleukin-4 (IL-4) and Toll-like receptor (TLR) ligand-activated transcriptional programs mutually antagonize each other, and no remarkable convergence has been identified between them. In contrast, here, we show that IL-4-polarized macrophages established a hyperinflammatory gene expression program upon lipopolysaccharide (LPS) exposure. This phenomenon, which we termed extended synergy, was supported by IL-4-directed epigenomic remodeling, LPS-activated NF-κB-p65 cistrome expansion, and increased enhancer activity. The EGR2 transcription factor contributed to the extended synergy in a macrophage-subtype-specific manner. Consequently, the previously alternatively polarized macrophages produced increased amounts of immune-modulatory factors both in vitro and in vivo in a murine Th2 cell-type airway inflammation model upon LPS exposure. Our findings establish that IL-4-induced epigenetic reprogramming is responsible for the development of inflammatory hyperresponsiveness to TLR activation and contributes to lung pathologies.

The changing extra‐ and intracellular microenvironment calls for rapid cell fate decisions that are precisely and primarily regulated at the transcriptional level. The cellular components of the immune system are excellent examples of how cells respond and adapt to different environmental stimuli. Innate immune cells such as macrophages are able to modulate their transcriptional programs and epigenetic regulatory networks through activation and repression of particular genes, allowing them to quickly respond to a rapidly changing environment. Tissue macrophages are essential components of different immune‐ and nonimmune cell‐mediated physiological mechanisms in mammals and are widely used models for investigating transcriptional regulatory mechanisms. Therefore, it is critical to unravel the distinct sets of transcription activators, repressors, and coregulators that play roles in determining tissue macrophage identity and functions during homeostasis, as well as in diseases affecting large human populations, such as metabolic syndromes, immune‐deficiencies, and tumor development. In this review, we will focus on transcriptional repressors that play roles in tissue macrophage development and function under physiological conditions.

Alveolar macrophages (AMs) act as gatekeepers of the lung’s immune responses, serving essential roles in recognizing and eliminating pathogens. The transcription factor (TF) early growth response 2 (EGR2) has been recently described as required for mature AMs in mice; however, its mechanisms of action have not been explored. Here, we identified EGR2 as an epigenomic regulator and likely direct proximal transcriptional activator in AMs using epigenomic approaches (RNA sequencing, ATAC sequencing, and CUT&RUN). The predicted direct proximal targets of EGR2 included a subset of AM identity genes and ones related to pathogen recognition, phagosome maturation, and adhesion, such as Clec7a , Atp6v0d2 , Itgb2 , Rhoc , and Tmsb10 . We provided evidence that EGR2 deficiency led to impaired zymosan internalization and reduced the capacity to respond to Aspergillus fumigatus . Mechanistically, the lack of EGR2 altered the transcriptional response, secreted cytokines (i.e., CXCL11), and inflammation-resolving lipid mediators (i.e., RvE1) of AMs during in vivo zymosan-induced inflammation, which manifested in impaired resolution. Our findings demonstrated that EGR2 is a key proximal transcriptional activator and epigenomic bookmark in AMs responsible for select, distinct components of cell identity and a protective transcriptional and epigenomic program against fungi.

Introduction: In this work we selected components, developed technology and studied a number of parameters of polymer nanocomposite materials, remembering that the material would have high optical and good mechanical characteristics, good sorption ability in order to ensure high value of the optical signal for a short time while maintaining the initial geometric shape. In addition, if this nanocomposite is used for medicine and biology (biocompatible or biocidal materials or the creation of a sensor based on it), the material must be non-toxic and/or biocompatible. We study the creation of polymer nanocomposites which may be applied as biocompatible materials with new functional parameters. Material and Methods: A number of polymer nanocomposites based on various urethane-acrylate monomers and nanoparticles of gold, silicon oxides, zinc and/or titanium oxides are obtained, their mechanical (microhardness) properties and wettability (contact angle) are studied. The set of required, biology-related properties of these materials, such as toxicity and sorption of microorganisms are also investigated in order to prove their possible applicability. Results and Discussion: The composition of the samples influences their microhardness and the value of contact angle, which means that varying with the monomer and the metallic, oxide nanoparticles composition, we could change these parameters. Besides it, the set of required, biology-related properties of these materials, such as toxicity and sorption of microorganisms were also investigated in order to prove their possible applicability. It was shown that the materials are non-toxic, the adhesion of microorganisms on their surface also could be varied by changing their composition. Conclusion: The presented polymer nanocomposites with different compositions of monomer and the presence of nanoparticles in them are prospective material for a possible bio-application as it is biocompatible, not toxic. The sorption of microorganism could be varied depending on the type of bacterias, the monomer composition, and nanoparticles.

Hofbauer cells (HBCs) are fetal macrophages located in the placenta that contribute to antimicrobial defense, angiogenesis, tissue remodeling, and metabolic processes within the chorionic villi. Although their roles in placental biology are increasingly recognized, the mechanisms that regulate HBC identity and function are not yet fully defined. This study aimed to define the core transcriptomic and epigenomic features of HBCs in term placentas and to examine their capacity for transcriptional responsiveness and phenotypic variation. Using chromatin accessibility profiling and bulk RNA-seq, we found that HBCs exhibit a unique gene expression and chromatin accessibility profile compared with other fetal and adult macrophages. We identified a coordinated transcriptional network involving nuclear receptors (NRs) NR4A1–3, the glucocorticoid receptor, and RFX family members (RFX1, RFX2, RFX5) that appears to shape HBC identity, particularly through pathways linked to lipid metabolism and angiogenesis. Although exploratory in nature, in vitro stimulation studies showed that HBCs exhibited increased transcriptional activity in response to combined IL-4 and rosiglitazone treatment, including induction of the lipid transporter CD36. Mass cytometry analysis revealed surface markers indicative of both immature and mature macrophage states. These results together indicate that HBCs are a distinct and diverse population of macrophages with a specialized, adaptable regulatory program in the human placenta.

Enormous diversity of commensal bacteria determines individual functions acting on the development and activities of the human immune system. These involve specialized macrophage and dendritic cell subsets, expression of unique pattern recognition receptor combinations coupled to evolutionally conserved signaling pathways, transcriptional regulation, post-translational modifications, induction of co-stimulatory molecules, secretion of cytokines, chemokines and type I interferons. This complexity can directly be translated to T-lymphocyte polarization to support tolerance induction or inflammation. We have developed a sensitive in vitro culture system for investigating the response of moDC subsets to commensal bacteria by monitoring the expression of type I/II CD1 proteins, phagocytic activity, secretion of chemokines, pro-inflammatory and T-cell polarizing cytokines. Under physiological conditions the gut microenvironment is conditioned by retinoic acid (ATRA) produced by intestinal epithelial cells and CD103+ DCs. To consider the impact of this special microenvironment on moDC-induced T-lymphocyte responses we compared the effects of selected microbes in absence and presence of ATRA. Selected microbes exerted their modulatory effects in a dose- and strain-dependent manner and ATRA had a significant impact on moDC-induced T-cell responses: • ATRA inhibited CD1a expression in moDCs without affecting CD83 expression; • Gene expression involved in retinoid synthesis was enhanced but microbes counter acted this effect; • Secretion of IL-1β concommitant with NOD2, NLRC4 and NLRP12 gene expression was dramatically enhanced by ATRA but microbes inhibited this effect; • Opposing activity of NOD2 to NLRC4 and NLRP12 pointed to an autocrine IL-1β-mediated regulation; • ATRA increased Th17 and decreased Th1 responses significantly.