Continuous Exposure to Non-Soluble ß-Glucans Induces Trained Immunity in M-CSF-Differentiated Macrophages.

Beta-glucans enable functional reprogramming of innate immune cells, a process defined as "trained immunity", which results in enhanced host responsiveness against primary (training) and/or secondary infections (resilience). Trained immunity holds great promise for promoting immune responses in groups that are at risk (e.g. elderly and patients). In this study, we modified an existing in vitro model for trained immunity by actively inducing monocyte-to-macrophage differentiation using M-CSF and applying continuous exposure. This model reflects mucosal exposure to ß-glucans and was used to study the training effects of a variety of soluble or non-soluble ß-glucans derived from different sources including oat, mushrooms and yeast. In addition, trained immunity effects were related to pattern recognition receptor usage, to which end, we analyzed ß-glucan-mediated Dectin-1 activation. We demonstrated that ß-glucans, with different sources and solubilities, induced training and/or resilience effects. Notably, trained immunity significantly correlated with Dectin-1 receptor activation, yet Dectin-1 receptor activation did not perform as a sole predictor for ß-glucan-mediated trained immunity. The model, as validated in this study, adds on to the existing in vitro model by specifically investigating macrophage responses and can be applied to select non-digestible dietary polysaccharides and other components for their potential to induce trained immunity.

Dermal bacterial LPS-stimulation reduces susceptibility to intradermal Trypanosoma brucei infection.

Infections with Trypanosoma brucei sp. are established after the injection of metacyclic trypomastigotes into the skin dermis by the tsetse fly vector. The parasites then gain access to the local lymphatic vessels to infect the local draining lymph nodes and disseminate systemically via the bloodstream. Macrophages are considered to play an important role in host protection during the early stage of systemic trypanosome infections. Macrophages are abundant in the skin dermis, but relatively little is known of their impact on susceptibility to intradermal (ID) trypanosome infections. We show that although dermal injection of colony stimulating factor 1 (CSF1) increased the local abundance of macrophages in the skin, this did not affect susceptibility to ID T. brucei infection. However, bacterial LPS-stimulation in the dermis prior to ID trypanosome infection significantly reduced disease susceptibility. In vitro assays showed that LPS-stimulated macrophage-like RAW264.7 cells had enhanced cytotoxicity towards T. brucei, implying that dermal LPS-treatment may similarly enhance the ability of dermal macrophages to eliminate ID injected T. brucei parasites in the skin. A thorough understanding of the factors that reduce susceptibility to ID injected T. brucei infections may lead to the development of novel strategies to help reduce the transmission of African trypanosomes.

Abraxane-induced bone marrow CD11b+ myeloid cell depletion in tumor-bearing mice is visualized by µPET-CT with 64Cu-labeled anti-CD11b and prevented by anti-CSF-1.

To investigate the utility of noninvasive µPET-CT with 64Cu-DOTA-anti-CD11b (64Cu-αCD11b) in assessing bone marrow status after anticancer therapies, and the protective role of anti-CSF-1 (αCSF-1) against bone marrow suppression induced by Abraxane. Methods: MDA-MB-435 tumor-bearing mice were treated with Abraxane, αCSF-1, or αCSF-1 plus Abraxane. µPET-CT and biodistribution of 64Cu-αCD11b were performed after intravenous injection of the radiotracer. Cells from mouse bone marrow and MDA-MB-435 tumor were analyzed by flow cytometry. A humanized αCSF-1 was investigated for its role in protecting bone marrow cells, using a transgenic mouse model that expresses functional human CSF-1. Results: µPET-CT showed that 64Cu-αCD11b had high uptake in the bone marrow and spleen of both normal and tumor-bearing mice. Abraxane significantly reduced 64Cu-αCD11b uptake in the bone marrow and spleen of treated mice compared to untreated mice. Interestingly, 64Cu-αCD11b µPET-CT revealed that αCSF-1 alleviated the depletion of bone marrow cells by Abraxane. These changes in the bone marrow population of CD11b+ myeloid cells were confirmed by flow cytometry. Moreover, αCSF-1 potently enhanced tolerance of bone marrow granulocytic myeloid cells to Abraxane, decreased cell migration, and suppressed recruitment of myeloid cells to the tumor microenvironment. The humanized αCSF-1 also alleviated the effects of Abraxane on bone marrow cells in transgenic mice expressing human CSF-1, suggesting clinical relevance of αCSF-1 in prevention of bone marrow suppression in addition to its role in reducing tumor-infiltrating myeloid cells. Conclusions: Abraxane-induced bone marrow CD11b+ myeloid cell depletion in tumor-bearing mice could be noninvasively assessed by µPET-CT with 64Cu-αCD11b and prevented by αCSF-1.

CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis.

Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma (DLBCL). However, the biological relevance of epigenetic gene mutations on tumor microenvironment remains to be determined. The core set of genes relating to histone methylation (KMT2D, KMT2C, EZH2), histone acetylation (CREBBP, EP300), DNA methylation (TET2), and chromatin remodeling (ARID1A) were detected in the training cohort of 316 patients by whole-genome/exome sequencing (WGS/WES) and in the validation cohort of 303 patients with newly diagnosed DLBCL by targeted sequencing. Their correlation with peripheral blood immune cells and clinical outcomes were assessed. Underlying mechanisms on tumor microenvironment were investigated both in vitro and in vivo. Among all 619 DLBCL patients, somatic mutations in KMT2D (19.5%) were most frequently observed, followed by mutations in ARID1A (8.7%), CREBBP (8.4%), KMT2C (8.2%), TET2 (7.8%), EP300 (6.8%), and EZH2 (2.9%). Among them, CREBBP/EP300 mutations were significantly associated with decreased peripheral blood absolute lymphocyte-to-monocyte ratios, as well as inferior progression-free and overall survival. In B-lymphoma cells, the mutation or knockdown of CREBBP or EP300 inhibited H3K27 acetylation, downregulated FBXW7 expression, activated the NOTCH pathway, and downstream CCL2/CSF1 expression, resulting in tumor-associated macrophage polarization to M2 phenotype and tumor cell proliferation. In B-lymphoma murine models, xenografted tumors bearing CREBBP/EP300 mutation presented lower H3K27 acetylation, higher M2 macrophage recruitment, and more rapid tumor growth than those with CREBBP/EP300 wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis. Our work thus contributed to the understanding of aberrant histone acetylation regulation on tumor microenvironment as an alternative mechanism of tumor progression in DLBCL.

Differential TLR7-mediated cytokine expression by R848 in M-CSF- versus GM-CSF-derived macrophages after LCMV infection.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) play an important role in macrophage (MФ) development by influencing their differentiation and polarization. Our goal was to explore the difference between M-CSF- and GM-CSF-derived bone marrow MФ responsiveness to TLR7-mediated signalling pathways that influence cytokine production early after infection in a model of acute virus infection. To do so, we examined cytokine production and TLR7-mediated signalling at 1 h post-lymphocytic choriomeningitis virus (LCMV) Armstrong (ARM) infection. We found that R848-induced cytokine expression was enhanced in these cells, with GM-CSF cells exhibiting higher proinflammatory cytokine expression and M-CSF cells exhibiting higher anti-inflammatory cytokine expression. However, R848-mediated signalling molecule activation was diminished in LCMV-infected M-CSF and GM-CSF macrophages. Interestingly, we observed that TLR7 expression was maintained during LCMV infection of M-CSF and GM-CSF cells. Moreover, TLR7 expression was significantly higher in M-CSF cells compared to GM-CSF cells. Taken together, our data demonstrate that although LCMV restrains early TLR7-mediated signalling, it primes differentiated MФ to enhance expression of their respective cytokine profiles and maintains levels of TLR7 expression early after infection.

Macrophage colony stimulating factor (MCSF) of Japanese flounder (Paralichthys olivaceus): Immunoregulatory property, anti-infectious function, and interaction with MCSF receptor.

Macrophage colony-stimulating factor (MCSF) is an essential growth factor to control the proliferation, differentiation and survival of the macrophage lineage in vertebrates. Sequences of MCSF have been identified in multiple teleost species, however, the functional investigations of MCSF were documented in only a few species. In this study, we examined the biological activity and the immunomodulatory property of a MCSF homologue, PoMCSF, from Japanese flounder (Paralichthys olivaceus). Structural analysis showed that PoMCSF possesses conserved structural characteristics of MCSF proteins, including a signal peptide, a CSF-1 domain, and a transmembrane region closed to the C-terminal. Under normal physiological condition, PoMCSF expression distributes in all the examined tissues, the highest three tissues are blood, muscle, and head kidney. When infected by extracellular and intracellular bacterial pathogens and viral pathogen, the PoMCSF expression patterns vary with different types of microbial pathogens infection and different immune tissues. In vitro experiment showed recombinant PoMCSF promoted the activity of macrophage. In vivo experiment indicated that PoMCSF overexpression boosted the defensive ability of flounder against Edwardsiella piscicida, a severe fish pathogen that infects multiple species of economically important fish, and regulated the expression of multiple immune-related genes. To explore the relationship between PoMCSF and its receptor PoMCSFR, anti-PoMCSFR antibody was prepared and PoMCSFR knockdown was conducted. The neutralization assay showed that when PoMCSFR was neutralized by its antibody, the role of PoMCSF on host defense against E. piscicida was weakened. Knockdown of PoMCSFR impaired the phagocytic capacity of macrophages. Collectively, these findings suggest that PoMCSF plays a crucial role in the immune defense system of Japanese flounder and the effect of PoMCSF is dependent on PoMCSFR. This study provides new insights into the biological activity of MCSF and the relationship between MCSF and MCSFR in teleost.

Tumor-associated macrophage polarization promotes the progression of esophageal carcinoma.

The immune response facilitated by tumor-associated macrophages is a vital determinant of tumor progression. We identified differentially expressed genes between various macrophage phenotypes in the Gene Expression Omnibus, and used Kaplan-Meier Plotter to determine which of them altered the prognosis of esophageal carcinoma patients. Fibrinogen-like protein 2 (FGL2), an immunosuppressive factor in the tumor microenvironment of various cancers, was upregulated in M2 macrophages, and higher FGL2 expression was associated with poorer survival in esophageal carcinoma patients. Using the TIMER database, we found that FGL2 expression correlated positively with the levels of immune markers of infiltrating B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells in esophageal carcinoma samples. Correlation analyses in cBioPortal revealed that the mRNA levels of FGL2 correlated strongly with those of interleukin 10, matrix metalloproteinase 9, C-C motif chemokine ligand 5, T-cell immunoglobulin mucin 3, interleukin 13, vascular cell adhesion molecule 1, macrophage colony-stimulating factor and fibroblast growth factor 7 in esophageal carcinoma tissues. The same cytokines were upregulated when esophageal squamous cell carcinoma cells were co-cultured with M2-like tumor-associated macrophages. Thus, by secreting FGL2, M2-like tumor-associated macrophages may create an immunosuppressive tumor microenvironment that induces the occurrence and progression of esophageal carcinoma.

Coating M-CSF on plastic surface results in the generation of increased numbers of macrophages in vitro.

Macrophages are one of the important cell types in the innate immune system that are present in various anatomical regions of the body and promote early control of pathogens. The relative proportion of macrophages in various lymphoid and non-lymphoid regions is small, and as such it is tedious to purify these cells to homogeneity. Culture of bone marrow precursors with macrophage colony-stimulating factor (M-CSF) results in their differentiation to macrophages, however this procedure results in low numbers of differentiated macrophages. Herein we reveal a new approach of generating increased numbers of differentiated macrophages from bone marrow precursors. We show that M-CSF delivered in a plate-bound form results in the differentiation of significantly more macrophages in comparison to soluble M-CSF. Furthermore, the macrophages differentiated with plate-bound M-CSF display increased metabolic activity and cell death following infection with pathogens.

Identification of a nerve-associated, lung-resident interstitial macrophage subset with distinct localization and immunoregulatory properties.

Tissue-resident macrophages are a diverse population of cells that perform specialized functions including sustaining tissue homeostasis and tissue surveillance. Here, we report an interstitial subset of CD169+ lung-resident macrophages that are transcriptionally and developmentally distinct from alveolar macrophages (AMs). They are primarily localized around the airways and are found in close proximity to the sympathetic nerves in the bronchovascular bundle. These nerve- and airway-associated macrophages (NAMs) are tissue resident, yolk sac derived, self-renewing, and do not require CCR2+ monocytes for development or maintenance. Unlike AMs, the development of NAMs requires CSF1 but not GM-CSF. Bulk population and single-cell transcriptome analysis indicated that NAMs are distinct from other lung-resident macrophage subsets and highly express immunoregulatory genes under steady-state and inflammatory conditions. NAMs proliferated robustly after influenza infection and activation with the TLR3 ligand poly(I:C), and in their absence, the inflammatory response was augmented, resulting in excessive production of inflammatory cytokines and innate immune cell infiltration. Overall, our study provides insights into a distinct subset of airway-associated pulmonary macrophages that function to maintain immune and tissue homeostasis.

Correlation Analysis of Morphological Changes of Structural and Functional Areas of Mesenteric Lymph Nodes with Cytokines of Lymph of Thoracic Lymphatic Duct in Experimental Breast Cancer.

We performed a correlation analysis of the morphometric parameters of mesenteric lymph nodes and cytokine content in the lymph of thoracic duct in rats with chemically induced breast cancer. The study showed that activity of the local immune response in the lymph nodes in breast cancer is aimed at antitumor protection. In breast cancer, the area of the paracortical zone remained at the level of the intact group, while the area of lymphoid nodules with germinative centers and the area of medullary substance increased; the number of macrophages in the thymus-dependent zone and zone responsible for humoral immunity also increased. The following positive correlations were revealed: in germinative centers and medullary substance, number of mitotic cells correlated with cytokine IL-5 content and the number of medium lymphocytes correlated with the content of chemokine MIP-1α; in the germinative centers, the number of immunoblasts correlated with the level of cytokine GRO/KC, in the paracortical zone, the number of macrophages correlated with the level of chemokine MCP-1, the number of reticular cells correlated with IL-6 and M-CSF content; in medullary substance, the number of small lymphocytes and mature cells plasma cells (their content was reduced) correlated with the level of chemokine GRO/KC, which can be caused by their migration from the lymph node.

Mudskipper interleukin-34 modulates the functions of monocytes/macrophages via the colony-stimulating factor-1 receptor 1.

Interleukin-34 (IL-34) is a novel cytokine that plays an important role in innate immunity and inflammatory processes by binding to the colony-stimulating factor-1 receptor (CSF-1R). However, information on the function of IL-34 in fish remains limited. In the present study, we identified an IL-34 homolog from mudskippers ( Boleophthalmus pectinirostris). In silico analysis showed that the mudskipper IL-34 (BpIL-34) was similar to other known IL-34 variants in sequence and structure and was most closely related to an orange-spotted grouper ( Epinephelus coioides) homolog. BpIL-34 transcripts were constitutively expressed in various tissues, with the highest level of expression found in the brain. Edwardsiella tarda infection significantly up-regulated the mRNA expression of BpIL-34 in the mudskipper tissues. The recombinant mature BpIL-34 peptide (rBpIL-34) was purified and used to produce anti-rBpIL-34 IgG. Western blot analysis combined with PNGase F digestion revealed that native BpIL-34 in monocytes/macrophages (MOs/MФs) was N-glycosylated. In vitro, rBpIL-34 treatment enhanced the phagocytotic and bactericidal activity of mudskipper MOs/MФs, as well as the mRNA expression of pro-inflammatory cytokines like tumor necrosis factor α ( BpTNF-α) and BpIL-1ß in these cells. Furthermore, the knockdown of mudskipper CSF-1R1 ( BpCSF-1R1), but not mudskipper BpCSF-1R2, significantly inhibited the rBpIL-34-mediated enhanced effect on MO/MФ function. In conclusion, our results indicate that mudskipper BpIL-34 modulates the functions of MOs/MФs via BpCSF-1R1.

Establishment and Maintenance of the Macrophage Niche.

Self-maintaining resident macrophages populate all mammalian organs. In addition to their role as immune sentinels, macrophages also perform day-to-day functions essential to tissue homeostasis. The homeostatic functions of macrophages are regulated by so-called tissular "niches" that control the size of the macrophage population and imprint tissue-specific identity. Here, we review the mechanisms underlying self-maintenance of distinct macrophage populations and outline the organizing principles of the macrophage niche. We examine recent studies that uncovered mutually beneficial cell-cell circuits established between macrophages and their niche and propose a modular view of tissues that integrates the resident macrophage as an essential component of each individual module. Manipulating macrophage niche cells to control the function of resident macrophages in vivo might have therapeutic value in various disease settings.

CSF1-associated decrease in endometrial macrophages may contribute to Asherman's syndrome.

PROBLEM: Asherman's syndrome (AS) is characterized by endometrial fibrosis leading to intrauterine adhesions and symptoms like hypomenorrhea, infertility, and recurrent pregnancy loss. Macrophages are key regulators of inflammation, tissue repair, regeneration, and fibrosis. However, the role of macrophages in AS remains unclear. METHOD OF STUDY: Endometrial biopsies of AS patients and controls were collected during the late proliferating phase of menstrual cycle. Fibrosis and proliferation markers were detected by Masson's trichrome staining and immunohistochemistry. Macrophages were examined by immunostaining and flow cytometry. The expression levels of CCL2, CSF1, CSF1R, and GM-CSF were detected by quantitative real-time polymerase chain reaction (q-PCR) and immunohistochemistry. A well-differentiated endometrial cell line Ishikawa (IK) was used for in vitro studies. Macrophages differentiating from THP-1 monocytic cells were polarized by IL-4/IL-13. Their culture supernatants (M(IL-4/13)-S) were applied to H2 O2 or bleomycin-damaged IK cells. RESULTS: In AS patients, endometrial stroma was replaced by fibrous tissue and cell proliferation was reduced. Macrophages in endometrial tissue were mainly alternative activated macrophages and their number was significantly decreased in AS patients. The CSF1 expression level was reduced in AS patients. M(IL-4/13)-S promoted the growth and migration of IK cells and inhibited H2 O2 -induced apoptosis. M(IL-4/13)-S protected IK cells from bleomycin-induced fibrosis. CONCLUSION: Macrophages are critical cells involved in the process of endometrial repair and fibrosis. The decreased amount of endometrial macrophages may be attributed to the reduced expression level of CSF1. Manipulation of macrophage activation/function may provide a novel therapeutic target for AS.

Who's in charge here? Macrophage colony stimulating factor and granulocyte macrophage colony stimulating factor: Competing factors in macrophage polarization.

Macrophages make up a crucial aspect of the immune system, carrying out a variety of functions ranging from clearing cellular debris to their well-recognized roles as innate immune cells. These cells exist along a spectrum of phenotypes but can be generally divided into proinflammatory (M1) and anti-inflammatory (M2) groups, representing different states of polarization. Due to their diverse functions, macrophages are implicated in a variety of diseases such as atherosclerosis, lupus nephritis, or infection with HIV. Throughout their lifetime, macrophages can be influenced by a wide variety of signals that influence their polarization states, which can affect their function and influence their effects on disease progression. This review seeks to provide a summary of how GM-CSF and M-CSF influence macrophage activity during disease, and provide examples of in vitro research that indicate competition between the two cytokines in governing macrophage polarization. Gaining a greater understanding of the relationship between GM-CSF and M-CSF, along with how these cytokines fit into the larger context of diseases, will inform their use as treatments or targets for treatment in various diseases.

Regulation and function of macrophage colony-stimulating factor (CSF1) in the chicken immune system.

Macrophage colony-stimulating factor (CSF1) is an essential growth factor to control the proliferation, differentiation and survival of cells of the macrophage lineage in vertebrates. We have previously produced a recombinant chicken CSF1-Fc fusion protein and administrated it to birds which produced a substantial expansion of tissue macrophage populations. To further study the biology of CSF1 in the chicken, here we generated anti-chicken CSF1 antibodies (ROS-AV181 and 183) using CSF1-Fc as an immunogen. The specific binding of each monoclonal antibody was confirmed by ELISA, Western blotting and immunohistochemistry on tissue sections. Using the anti-CSF1 antibodies, we show that chicken bone marrow derived macrophages (BMDM) express CSF1 on their surface, and that the level appears to be regulated further by exogenous CSF1. By capture ELISA circulating CSF1 levels increased transiently in both layer and broiler embryos around the day of hatch. The levels of CSF1 in broilers was higher than in layers during the first week after hatch. Antibody ROS-AV183 was able to block CSF1 biological activity in vitro and treatment of hatchlings using this neutralising antibody in vivo impacted on some tissue macrophage populations, but not blood monocytes. After anti-CSF1 treatment, CSF1R-transgene reporter expressing cells were reduced in the bursa of Fabricius and cecal tonsil and TIM4+ Kupffer cells in the liver were almost completely ablated. Anti-CSF1 treatment also produced a reduction in overall bone density, trabecular volume and TRAP+ osteoclasts. Our novel neutralising antibody provides a new tool to study the roles of CSF1 in birds.

CSF1R Ligands IL-34 and CSF1 Are Differentially Required for Microglia Development and Maintenance in White and Gray Matter Brain Regions.

Microglia are specialized brain macrophages that play numerous roles in tissue homeostasis and response to injury. Colony stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase required for the development, maintenance, and proliferation of microglia. Here we show that in adult mice peripheral dosing of function-blocking antibodies to the two known ligands of CSF1R, CSF1, and IL-34, can deplete microglia differentially in white and gray matter regions of the brain, respectively. The regional patterns of depletion correspond to the differential expression of CSF1 and IL-34. In addition, we show that while CSF1 is required to establish microglia in the developing embryo, both CSF1 and IL-34 are required beginning in early postnatal development. These results not only clarify the roles of CSF1 and IL-34 in microglia maintenance, but also suggest that signaling through these two ligands might support distinct sub-populations of microglia, an insight that may impact drug development for neurodegenerative and other diseases.

Function of CSF1 and IL34 in Macrophage Homeostasis, Inflammation, and Cancer.

Colony-stimulating factor 1 (CSF1) and interleukin 34 (IL34) signal via the CSF1 receptor to regulate macrophage differentiation. Studies in IL34- or CSF1-deficient mice have revealed that IL34 function is limited to the central nervous system and skin during development. However, the roles of IL34 and CSF1 at homeostasis or in the context of inflammatory diseases or cancer in wild-type mice have not been clarified in vivo. By neutralizing CSF1 and/or IL34 in adult mice, we identified that they play important roles in macrophage differentiation, specifically in steady-state microglia, Langerhans cells, and kidney macrophages. In several inflammatory models, neutralization of both CSF1 and IL34 contributed to maximal disease protection. However, in a myeloid cell-rich tumor model, CSF1 but not IL34 was required for tumor-associated macrophage accumulation and immune homeostasis. Analysis of human inflammatory conditions reveals IL34 upregulation that may account for the protection requirement of IL34 blockade. Furthermore, evaluation of IL34 and CSF1 blockade treatment during Listeria infection reveals no substantial safety concerns. Thus, IL34 and CSF1 play non-redundant roles in macrophage differentiation, and therapeutic intervention targeting IL34 and/or CSF1 may provide an effective treatment in macrophage-driven immune-pathologies.

Hypercalcaemia secondary to disseminated Mycobacterium abscessus and Mycobacterium fortuitum.

The incidence and prevalence of nontuberculous mycobacteria (NTM) infection is on the rise with many cases still going unreported. Given the vague and nonspecific clinical features of NTM infections, it is often missed or mistaken for Mycobacterium tuberculosis. The presumption that NTM infections are benign and do not contribute to morbidity no longer holds true. NTM infections need to be considered in patients with disseminated multisystem disease and in those not responding to standard M. tuberculosis treatment. As NTM infection is associated with granuloma formation, it can result in hypercalcaemia. Interestingly, there is evidence that there may be other mechanisms in play contributing to hypercalcaemia besides the increased calcitriol levels.

Targeting IL-34 in inflammatory autoimmune diseases.

Interleukin-34 (IL-34) shares a common receptor with macrophage colony-stimulating factor (M-CSF), and can bind to CSF-1R, induces lymphocytes differentiation, proliferation, and regulates the synthesis of inflammatory components. Recent findings reported aberrant expression of IL-34 in several autoimmune disorders, such as lupus, arthritis, systemic sclerosis, inflammatory bowel diseases. The functional analysis further demonstrated that IL-34 may perform significantly in these inflammatory autoimmune disorders. IL-34 might consider as a biomarker for these diseases. I hope this collection of the findings in this review will improve knowledge of the role of IL-34, and targeting IL-34 may give the potential for these autoimmune diseases.

Interleukin-34 drives macrophage polarization to the M2 phenotype in autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis is a chronic inflammatory disease, the abnormal immunological function is the main pathogenesis. Interleukin-34 is a newly identified cytokine that shares the same receptor as colony stimulating factor-1. METHODS: We used interleukin-34 knockout and wild-type mice in a Con A-induced hepatitis model and cocultured RAW264.7 macrophage cells with interleukin-34. We then detected associated inflammatory cytokine and chemokine levels to elucidate the role of interleukin-34. RESULTS: In this study, we found that the loss of interleukin-34 resulted in higher sensitivity to Con A-induced hepatitis. RAW264.7 macrophage cells were able to differentiate to the M2 phenotype upon interleukin-34 stimulation. CONCLUSIONS: We conclude that interleukin-34 may protect the liver from Con A-mediated hepatitis by driving M2 macrophage polarization and suppressing inflammation.