IL-9 has been reported to play dual roles in the pathogenesis of autoimmune disorders and cancers. The collaboration of IL-9 with microenvironmental factors including the broader cytokine milieu and other cellular components may provide important keys to explain its conflicting effects in chronic conditions. In this review, we summarize recent findings on the cellular sources of, and immunological responders to IL-9, in order to interpret the role of IL-9 in the regulation of immune responses. This knowledge will provide new perspectives to improve clinical benefits and limit adverse effects of IL-9 when treating pathologic conditions.

The protein encoded by the Gene Associated with Retinoid-Interferon-Induced Mortality-19 (GRIM-19) is located in the mitochondrial inner membrane and is homologous to the NADH dehydrogenase 1-alpha subcomplex subunit 13 of the electron transport chain. Multiple sclerosis (MS) is a demyelinating disease that damages the brain and spinal cord. Although both the cause and mechanism of MS progression remain unclear, it is accepted that an immune disorder is involved. We explored whether GRIM-19 ameliorated MS by increasing the levels of inflammatory cytokines and immune cells; we used a mouse model of experimental autoimmune encephalomyelitis (EAE) to this end. Six-to-eight-week-old male C57BL/6, IFNγ-knockout (KO), and GRIM-19 transgenic mice were used; EAE was induced in all strains. A GRIM-19 overexpression vector (GRIM19 OVN) was electrophoretically injected intravenously. The levels of Th1 and Th17 cells were measured via flow cytometry, immunofluorescence, and immunohistochemical analysis. IL-17A and IFNγ expression levels were assessed via ELISA and quantitative PCR. IL-17A expression decreased and IFNγ expression increased in EAE mice that received injections of the GRIM19 OVN. GRIM-19 transgenic mice expressed more IFNγ than did wild-type mice; this inhibited EAE development. However, the effect of GRIM-19 overexpression on the EAE of IFNγ-KO mice did not differ from that of the empty vector. GRIM-19 expression was therapeutic for EAE mice, elevating the IFNγ level. GRIM-19 regulated the Th17/Treg cell balance.

In the progression of atherosclerosis, macrophages are the key immune cells for foam cell formation. During hyperlipidemic condition, phagocytic cells such as monocytes and macrophages uptake oxidized low-density lipoproteins (oxLDLs) accumulated in subintimal space, and lipid droplets are accumulated in their cytosols. In this review, we discussed the characteristics and phenotypic changes of macrophages in atherosclerosis and the effect of cytosolic lipid accumulation on macrophage phenotype. Due to macrophage plasticity, the inflammatory phenotypes triggered by oxLDL can be re-programmed by cytosolic lipid accumulation, showing downregulation of NF-κB activation followed by activation of anti-inflammatory genes, leading to tissue repair and homeostasis. We also discuss about various in vivo and in vitro models for atherosclerosis research and next generation sequencing technologies for foam cell gene expression profiling. Analysis of the phenotypic changes of macrophages during the progression of atherosclerosis with adequate approach may lead to exact understandings of the cellular mechanisms and hint therapeutic targets for the treatment of atherosclerosis.

We investigated effects of reblastatins on phenotypic changes in monocytes/macrophages induced by 27-hydroxycholesterol (27OHChol). Treatment of THP-1 monocytic cells with reblastatin derivatives, such as 17-demethoxy-reblastatin (17-DR), 18-dehydroxyl-17-demethoxyreblastatin (WK88-1), 18-hydroxyl-17-demethoxyreblastatin (WK88-2), and 18-hydroxyl-17-demethoxy-4,5-dehydroreblastatin (WK88-3), resulted in blockage of CCL2, CCL3, and CCL4 expression at the transcription and protein levels, which, in turn, impaired migration of monocytes/macrophages and Jurkat T cells expressing CCR5, and almost complete inhibition of transcription of M1 marker cytokines, like CXCL10, CXCL11, and TNF-α. Reblastatins also downregulated surface CD14 as well as soluble CD14 along with inhibition of LPS response and matrix metalloprotease-9 expression. Surface levels of mature dendritic cell (mDC)-specific markers, including CD80, CD83, CD88, CD197, and MHC class I and II molecules, were remarkably down-regulated, and 27OHChol-induced decrease of endocytic activity was recovered following treatment with 17-DR, WK88-1, WK88-2, and WK88-3. However, 15-hydroxyl-17-demethoxyreblastatin (DHQ3) did not affect the molecular or functional changes in monocytic cells induced by 27OHChol. Furthermore, surface levels of CD105, CD137, and CD166 were also down-regulated by 17-DR, WK88-1, WK88-2, and WK88-3, but not by DHQ3. Collectively, results of the current study indicate that, except DHQ3, reblastatins regulate the conversion and differentiation of monocytic cells to an immunostimulatory phenotype and mDCs, respectively, which suggests possible applications of reblastatins for immunomodulation in a milieu rich in oxygenated cholesterol molecules.

With the development of technologies that can transform immune cells into therapeutic modalities, immunotherapy has remarkably changed the current paradigm of cancer treatment in recent years. NK cells are components of the innate immune system that act as key regulators and exhibit a potent tumor cytolytic function. Unlike T cells, NK cells exhibit tumor cytotoxicity by recognizing non-self, without deliberate immunization or activation. Currently, researchers have developed various approaches to improve the number and anti-tumor function of NK cells. These approaches include the use of cytokines and Abs to stimulate the efficacy of NK cell function, adoptive transfer of autologous or allogeneic ex vivo expanded NK cells, establishment of homogeneous NK cell lines using the NK cells of patients with cancer or healthy donors, derivation of NK cells from induced pluripotent stem cells (iPSCs), and modification of NK cells with cutting-edge genetic engineering technologies to generate chimeric Ag receptor (CAR)-NK cells. Such NK cell-based immunotherapies are currently reported as being promising anti-tumor strategies that have shown enhanced functional specificity in several clinical trials investigating malignant tumors. Here, we summarize the recent advances in NK cell-based cancer immunotherapies that have focused on providing improved function through the use of the latest genetic engineering technologies. We also discuss the different types of NK cells developed for cancer immunotherapy and present the clinical trials being conducted to test their safety and efficacy.

Type 2 diabetic nephropathy (T2DN) progresses with an increasingly inflammatory milieu, wherein various immune cells are relevant. Herein, we investigated the levels of myeloid-derived suppressor cells (MDSCs) and their clinical implication in patients with T2DN. A total of 91 subjects (T2DN, n=80; healthy, n=11) were recruited and their PBMCs were used for flow cytometric analysis of polymorphonuclear (PMN-) and monocytic (M-) MDSCs, in addition to other immune cell subsets. The risk of renal progression was evaluated according to the quartiles of MDSC levels using the Cox model. The proportion of MDSCs in T2DN patients was higher than in healthy individuals (median, 6.7% vs. 2.5%). PMN-MDSCs accounted for 96% of MDSCs, and 78% of PMN-MDSCs expressed Lox-1. The expansion of PMN-MDSCs was not related to the stage of T2DN or other kidney disease parameters such as glomerular filtration rate and proteinuria. The production of ROS in PMN-MDSCs of patients was higher than in neutrophils of patients or in immune cells of healthy individuals, and this production was augmented under hyperglycemic conditions. The 4th quartile group of PMN-MDSCs had a higher risk of renal progression than the 1st quartile group, irrespective of adjusting for multiple clinical and laboratory variables. In conclusion, PMN-MDSCs are expanded in patients with T2DN, and may represent as an immunological biomarker of renal progression.

An excessive hyperinflammatory response-caused septic shock is a major medical problem that is associated with pathogenic bacterial infections leading to high mortality rates. The intestinal microbiota and the associated elaborated metabolites such as short chain fatty acid butyrate have been shown to relieve pathogenic bacterial-caused acute inflammation. Butyrate can down-regulate inflammation by inhibiting the growth of pathobionts, increasing mucosal barrier integrity, encouraging obligate anaerobic bacterial dominance and decreasing oxygen availability in the gut. Butyrate can also decrease excessive inflammation through modulation of immune cells such as increasing functionalities of M2 macrophages and regulatory T cells and inhibiting infiltration by neutrophils. Therefore, various approaches can be used to increase butyrate to relieve pathogenic bacterial-caused hyperinflammation. In this review we summarize the roles of butyrate in attenuating pathogenic bacterial-caused hyperinflammatory responses and discuss the associated plausible mechanisms.

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that initiate both T-cell responses and tolerance. Tolerogenic DCs (tDCs) are regulatory DCs that suppress immune responses through the induction of T-cell anergy and Tregs. Because lactoferrin (LF) was demonstrated to induce functional Tregs and has a protective effect against inflammatory bowel disease, we explored the tolerogenic effects of LF on mouse bone marrow-derived DCs (BMDCs). The expression of CD80/86 and MHC class II was diminished in LF-treated BMDCs (LF-BMDCs). LF facilitated BMDCs to suppress proliferation and elevate Foxp3+ induced Treg (iTreg) differentiation in ovalbumin-specific CD4+ T-cell culture. Foxp3 expression was further increased by blockade of the B7 molecule using CTLA4-Ig but was diminished by additional CD28 stimulation using anti-CD28 Ab. On the other hand, the levels of arginase-1 and indoleamine 2,3-dioxygenase-1 (known as key T-cell suppressive molecules) were increased in LF-BMDCs. Consistently, the suppressive activity of LF-BMDCs was partially restored by inhibitors of these molecules. Collectively, these results suggest that LF effectively causes DCs to be tolerogenic by both the suppression of T-cell proliferation and enhancement of iTreg differentiation. This tolerogenic effect of LF is due to the reduction of costimulatory molecules and enhancement of suppressive molecules.

Vitamin D signaling plays an essential role in innate defense against intracellular microorganisms via the generation of the antimicrobial protein cathelicidin. In addition to directly binding to and killing a range of pathogens, cathelicidin acts as a secondary messenger driving vitamin D-mediated inflammation during infection. Recent studies have elucidated the biological and clinical functions of cathelicidin in the context of vitamin D signaling. The vitamin D-cathelicidin axis is involved in the activation of autophagy, which enhances antimicrobial effects against diverse pathogens. Vitamin D studies have also revealed positive and negative regulatory effects of cathelicidin on inflammatory responses to pathogenic stimuli. Diverse innate and adaptive immune signals crosstalk with functional vitamin D receptor signals to enhance the role of cathelicidin action in cell-autonomous effector systems. In this review, we discuss recent findings that demonstrate how the vitamin D-cathelicidin pathway regulates autophagy machinery, protective immune defenses, and inflammation, and contributes to immune cooperation between innate and adaptive immunity. Understanding how the vitamin D-cathelicidin axis operates in the host response to infection will create opportunities for the development of new therapeutic approaches against a variety of infectious diseases.

TLRs are pattern recognition receptors (PRRs) whose cytoplasmic signalling domain is similar to that of IL-1. The extracellular domain of TLRs serve as the binding site of pathogen associated molecular patterns. TLRs are found on both plasma and endosomal membranes and they mainly exert their function by activating genes which lead to production of inflammatory factors. The latest TLR to be discovered, TLR10 is a unique TLR which exhibit anti-inflammatory properties. TLR10 is found on the plasma membrane with other TLRs namely TLR1, TLR2, TLR4, TLR5 and TLR6. Studies have revealed that TLR10 is found on the same gene cluster with TLR1 and TLR6 and is also a coreceptor of TLR2. Up to date, TLR10 is the only TLR which exhibit anti-inflammatory property. Previously, TLR10 was thought to be an “orphan receptor” but much recent studies have identified ligands for TLR10. Currently there is no review article on TLR10 that has been published. In this narrative review, we are going to give an account of TLR10, its functions mainly as an anti-inflammatory PRR and its possible applications as a target in therapeutics.