Inflammation-induced Id2 promotes plasticity in regulatory T cells

T(H)17 cells originating from regulatory T (T-reg) cells upon loss of the T-reg-specific transcription factor Foxp3 accumulate in sites of inflammation and aggravate autoimmune diseases. Whether an active mechanism drives the generation of these pathogenic 'ex-Foxp3 T(H)17' cells, remains unclear. Here we show that pro-inflammatory cytokines enhance the expression of transcription regulator Id2, which mediates cellular plasticity of T-reg into 'ex-Foxp3' T(H)17 cells. Expression of Id2 in in vitro differentiated iT(reg) cells reduces the expression of Foxp3 by sequestration of the transcription activator E2A, leading to the induction of T(H)17-related cytokines. T-reg-specific ectopic expression of Id2 in mice significantly reduces the T-reg compartment and causes immune dysregulation. Cellular fate-mapping experiments reveal enhanced T-reg plasticity compared to wild-type, resulting in exacerbated experimental autoimmune encephalomyelitis pathogenesis or enhanced anti-tumor immunity. Our findings suggest that controlling Id2 expression may provide a novel approach for effective T-reg cell immunotherapies for both autoimmunity and cancer.11sciescopu

Inflammation-induced Id2 promotes plasticity in regulatory T cells

Regulatory T (Treg) cells may lose the expression of their master transcription factor, Foxp3, and be converted to pro-inflammatory cells. Here the authors show that this lineage plasticity may be mediated by the enhanced expression of another transcription regulator, Id2, which suppresses the transcription of Foxp3 to alter Treg lineage stability

Lowering <i>n</i>-6/<i>n</i>-3 Ratio as an Important Dietary Intervention to Prevent LPS-Inducible Dyslipidemia and Hepatic Abnormalities in <i>ob/ob</i> Mice

Obesity is closely associated with low-grade chronic and systemic inflammation and dyslipidemia, and the consumption of omega-3 polyunsaturated fatty acids (n-3 PUFAs) may modulate obesity-related disorders, such as inflammation and dyslipidemia. An emerging research question is to understand the dietary intervention strategy that is more important regarding n-3 PUFA consumption: (1) a lower ratio of n-6/n-3 PUFAs or (2) a higher amount of n-3 PUFAs consumption. To understand the desirable dietary intervention method of n-3 PUFAs consumption, we replaced lard from the experimental diets with either perilla oil (PO) or corn oil (CO) to have identical n-3 amounts in the experimental diets. PO had a lower n-6/n-3 ratio, whereas CO contained higher amounts of PUFAs; it inherently contained relatively lower n-3 but higher n-6 PUFAs than PO. After the 12-week dietary intervention in ob/ob mice, dyslipidemia was observed in the normal chow and CO-fed ob/ob mice; however, PO feeding increased the high density lipoprotein-cholesterol (HDL-C) level; further, not only did the HDL-C level increase, the low density lipoprotein-cholesterol (LDL-C) and triglyceride (TG) levels also decreased significantly after lipopolysaccharide (LPS) injection. Consequently, extra TG accumulated in the liver and white adipose tissue (WAT) of normal chow- or CO-fed ob/ob mice after LPS injection; however, PO consumption decreased serum TG accumulation in the liver and WAT. PUFAs replacement attenuated systemic inflammation induced by LPS injection by increasing anti-inflammatory cytokines but inhibiting pro-inflammatory cytokine production in the serum and WAT. PO further decreased hepatic inflammation and fibrosis in comparison with the ND and CO. Hepatic functional biomarkers (aspartate aminotransferase (AST) and alanine transaminase (ALT) levels) were also remarkably decreased in the PO group. In LPS-challenged ob/ob mice, PO and CO decreased adipocyte size and adipokine secretion, with a reduction in phosphorylation of MAPKs compared to the ND group. In addition, LPS-inducible endoplasmic reticulum (ER) and oxidative stress decreased with consumption of PUFAs. Taken together, PUFAs from PO and CO play a role in regulating obesity-related disorders. Moreover, PO, which possesses a lower ratio of n-6/n-3 PUFAs, remarkably alleviated metabolic dysfunction in LPS-induced ob/ob mice. Therefore, an interventional trial considering the ratio of n-6/n-3 PUFAs may be desirable for modulating metabolic complications, such as inflammatory responses and ER stress in the circulation, liver, and/or WAT

Resolving the Mutually Exclusive Immune Responses of Chitosan with Nanomechanics and Immunological Assays

Multifaceted functions displayed by both pro- and anti-inflammatory properties of chitosan hinder its effective development as an immunomodulatory agent. Herein, the contributions of the bending stiffness of chitosan with regard to its immune regulatory properties toward inflammation are investigated. The anti-inflammatory properties of chitosan molecular weight (MW) with a shorter (approximate to 1 kDa) or longer (approximate to 15 kDa) than the persistent length (L-P) are compared using immunological assays and nanomechanics-based experiments on the surface forces apparatus (SFA). Interestingly, 1 kDa chitosan significantly enhances the generation of anti-inflammatory regulatory T cells (Tregs) through the Dectin-1-dependent pattern recognition receptor (PRR) on antigen-presenting cells. SFA analyses also show a similar trend of interaction forces between chitosan and diverse PRRs depending on their MW. The results obtained in the immunological and nanomechanical experiments are consistent and imply that the binding features of PRRs vary depending on the MW of chitosan, which may alter immune activity. In accordance, in vivo administration of only 1 kDa represses inflammatory responses and suppresses the progression of experimental colitis. This study elucidates a previously unexplored bending stiffness-dependent immune regulatory property of chitosan and suggests the applicability of low MW (rod-like) chitosan as a pharmaceutical ingredient to treat diverse inflammatory disorders.11Nsciescopu

Anticoagulation therapy promotes the tumor immune-microenvironment and potentiates the efficacy of immunotherapy by alleviating hypoxia

Purpose Here, this study verifies that cancer-associated thrombosis (CAT) accelerates hypoxia, which is detrimental to the tumor immune microenvironment by limiting tumor perfusion. Therefore, we designed an oral anticoagulant therapy to improve the immunosuppressive tumor microenvironment and potentiate the efficacy of immunotherapy by alleviating tumor hypoxia. Experimental design A novel oral anticoagulant (STP3725) was developed to consistently prevent CAT formation. Tumor perfusion and hypoxia were analyzed with or without treating STP3725 in wild-type and P selectin knockout mice. Immunosuppressive cytokines and cells were analyzed to evaluate the alteration of the tumor microenvironment. Effector lymphocyte infiltration in tumor tissue was assessed by congenic CD45.1 mouse lymphocyte transfer model with or without anticoagulant therapy. Finally, various tumor models including K-Ras mutant spontaneous cancer model were employed to validate the role of the anticoagulation therapy in enhancing the efficacy of immunotherapy. Results CAT was demonstrated to be one of the perfusion barriers, which fosters immunosuppressive microenvironment by accelerating tumor hypoxia. Consistent treatment of oral anticoagulation therapy was proved to promote tumor immunity by alleviating hypoxia. Furthermore, this resulted in decrease of both hypoxia-related immunosuppressive cytokines and myeloid-derived suppressor cells while improving the spatial distribution of effector lymphocytes and their activity. The anticancer efficacy of alpha PD-1 antibody was potentiated by co-treatment with STP3725, also confirmed in various tumor models including the K-Ras mutant mouse model, which is highly thrombotic. Conclusions Collectively, these findings establish a rationale for a new and translational combination strategy of oral anticoagulation therapy with immunotherapy, especially for treating highly thrombotic cancers. The combination therapy of anticoagulants with immunotherapies can lead to substantial improvements of current approaches in the clinic.Y

Structural specificities of cell surface β-glucan polysaccharides determine commensal yeast mediated immuno-modulatory activities

Yeast is an integral part of mammalian microbiome, and like commensal bacteria, has the potential of being harnessed to influence immunity in clinical settings. However, functional specificities of yeast-derived immunoregulatory molecules remain elusive. Here we find that while under steady state, β-1,3-glucan-containing polysaccharides potentiate pro-inflammatory properties, a relatively less abundant class of cell surface polysaccharides, dubbed mannan/β-1,6-glucan-containing polysaccharides (MGCP), is capable of exerting potent anti-inflammatory effects to the immune system. MGCP, in contrast to previously identified microbial cell surface polysaccharides, through a Dectin1-Cox2 signaling axis in dendritic cells, facilitates regulatory T (Treg) cell induction from naïve T cells. Furthermore, through a TLR2-dependent mechanism, it restrains Th1 differentiation of effector T cells by suppressing IFN-γ expression. As a result, administration of MGCP display robust suppressive capacity towards experimental inflammatory disease models of colitis and experimental autoimmune encephalomyelitis (EAE) in mice, thereby highlighting its potential therapeutic utility against clinically relevant autoimmune diseases.11Ysciescopu

Cell surface polysaccharides of Bifidobacterium bifidum induce the generation of Foxp3(+) regulatory T cells

Dysregulation of intestinal microflora is linked to inflammatory disorders associated with compromised immunosuppressive functions of Foxp3(+) T regulatory (T-r(eg)) cells. Although mucosa-associated commensal microbiota has been implicated in T-reg generation, molecular identities of the "effector" components controlling this process remain largely unknown. Here, we have defined Bifidobacterium bifidum as a potent inducer of Foxp3(+) T-reg cells with diverse T cell receptor specificity to dietary antigens, commensal bacteria, and B. bifidum itself. Cell surface beta-glucan/galactan (CSGG) polysaccharides of B. bifidum were identified as key components responsible for T-reg induction. CSGG efficiently recapitulated the activity of whole bacteria and acted via regulatory dendritic cells through a partially Toll-like receptor 2-mediated mechanism. T-reg cells induced by B. bifidum or purified CSGG display stable and robust suppressive capacity toward experimental colitis. By identifying CSGG as a functional component of T-reg-inducing bacteria, our studies highlight the immunomodulatory potential of CSGG and CSGG-producing microbes © The Author