Cytosolic DNA sensing via the stimulator of IFN genes (STING) adaptor incites autoimmunity by inducing type I IFN (IFN-αβ). In this study, we show that DNA is also sensed via STING to suppress ...immunity by inducing IDO. STING gene ablation abolished IFN-αβ and IDO induction by dendritic cells (DCs) after DNA nanoparticle (DNP) treatment. Marginal zone macrophages, some DCs, and myeloid cells ingested DNPs, but CD11b(+) DCs were the only cells to express IFN-β, whereas CD11b(+) non-DCs were major IL-1β producers. STING ablation also abolished DNP-induced regulatory responses by DCs and regulatory T cells, and hallmark regulatory responses to apoptotic cells were also abrogated. Moreover, systemic cyclic diguanylate monophosphate treatment to activate STING induced selective IFN-β expression by CD11b(+) DCs and suppressed Th1 responses to immunization. Thus, previously unrecognized functional diversity among physiologic innate immune cells regarding DNA sensing via STING is pivotal in driving immune responses to DNA.
Cytosolic DNA sensing activates the stimulator of IFN genes (STING) adaptor to induce IFN type I (IFN-αβ) production. Constitutive DNA sensing to induce sustained STING activation incites tolerance ...breakdown, leading to autoimmunity. In this study, we show that systemic treatments with DNA nanoparticles (DNPs) induced potent immune regulatory responses via STING signaling that suppressed experimental autoimmune encephalitis (EAE) when administered to mice after immunization with myelin oligodendrocyte glycoprotein (MOG), at EAE onset, or at peak disease severity. DNP treatments attenuated infiltration of effector T cells into the CNS and suppressed innate and adaptive immune responses to myelin oligodendrocyte glycoprotein immunization in spleen. Therapeutic responses were not observed in mice treated with cargo DNA or cationic polymers alone, indicating that DNP uptake and cargo DNA sensing by cells with regulatory functions was essential for therapeutic responses to manifest. Intact STING and IFN-αβ receptor genes, but not IFN-γ receptor genes, were essential for therapeutic responses to DNPs to manifest. Treatments with cyclic diguanylate monophosphate to activate STING also delayed EAE onset and reduced disease severity. Therapeutic responses to DNPs were critically dependent on IDO enzyme activity in hematopoietic cells. Thus, DNPs and cyclic diguanylate monophosphate attenuate EAE by inducing dominant T cell regulatory responses via the STING/IFN-αβ/IDO pathway that suppress CNS-specific autoimmunity. These findings reveal dichotomous roles for the STING/IFN-αβ pathway in either stimulating or suppressing autoimmunity and identify STING-activating reagents as a novel class of immune modulatory drugs.
TLR ligands are effective vaccine adjuvants because they stimulate robust proinflammatory and immune effector responses and they abrogate suppression mediated by regulatory T cells (Tregs). ...Paradoxically, systemic administration of high doses of CpGs that bind to TLR9 ligands stimulated Tregs in mouse spleen to acquire potent suppressor activity dependent on interactions between programmed death-1 and its ligands. This response to CpG treatment manifested 8-12 h and was mediated by a rare population of plasmacytoid dendritic cells (CD19(+) pDC) induced to express the immunosuppressive enzyme IDO after TLR9 ligation. When IDO was blocked, CpG treatment did not activate Tregs, but instead stimulated pDCs to uniformly express the proinflammatory cytokine IL-6, which in turn reprogrammed Foxp3-lineage Tregs to express IL-17. Thus, CpG-induced IDO activity in pDCs acted as a pivotal molecular switch that induced Tregs to acquire a stable suppressor phenotype, while simultaneously blocking CpG-induced IL-6 expression required to reprogram Tregs to become Th17-like effector T cells. These findings support the hypothesis that IDO dominantly controls the functional status of Tregs in response to inflammatory stimuli in physiological settings.
Reagents that activate the signaling adaptor stimulator of interferon genes (STING) suppress experimentally induced autoimmunity in murine models of multiple sclerosis and arthritis. In this study, ...we evaluated STING agonists as potential reagents to inhibit spontaneous autoimmune type I diabetes (T1D) onset in non‐obese diabetic (NOD) female mice. Treatments with DNA nanoparticles (DNPs), which activate STING when cargo DNA is sensed, delayed T1D onset and reduced T1D incidence when administered before T1D onset. DNP treatment elevated indoleamine 2,3 dioxygenase (IDO) activity, which regulates T‐cell immunity, in spleen, pancreatic lymph nodes and pancreas of NOD mice. Therapeutic responses to DNPs were partially reversed by inhibiting IDO and DNP treatment synergized with insulin therapy to further delay T1D onset and reduce T1D incidence. Treating pre‐diabetic NOD mice with cyclic guanyl‐adenyl dinucleotide (cGAMP) to activate STING directly delayed T1D onset and stimulated interferon‐αβ (IFN‐αβ), while treatment with cyclic diguanyl nucleotide (cdiGMP) did not delay T1D onset or induce IFN‐αβ in NOD mice. DNA sequence analyses revealed that NOD mice possess a STING polymorphism that may explain differential responses to cGAMP and cdiGMP. In summary, STING agonists attenuate T1D progression and DNPs enhance therapeutic responses to insulin therapy.
Treatment with DNA nanoparticles (DNPs) to activate the Stimulator of Interferon Genes (STING) adaptor delays type I diabetes (T1D) progression in non‐obese diabetic (NOD) mice through a mechanism dependent in part on indoleamine 2,3‐dioxygenase (IDO). DNPs synergized with insulin therapy to slow T1D progression and reduce T1D incidence, while direct activation of STING by cyclic‐dinucleotides also delayed T1D onset and incidence. This study validates the ability of STING agonists to regulate autoimmunity and provides novel insights on how to optimize therapy with these reagents.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Topical application of phorbol myristate acetate (PMA) elicits intense local inflammation that facilitates outgrowth of premalignant lesions in skin after carcinogen exposure. The inflammatory ...response to PMA treatment activates immune stimulatory mechanisms. However, we show here that PMA exposure also induces plasmacytoid dendritic cells (pDCs) in local draining lymph nodes (dLNs) to express indoleamine 2,3 dioxygenase (IDO), which confers T cell suppressor activity on pDCs. The induced IDO-mediated inhibitory activity in this subset of pDCs was potent, dominantly suppressing the T cell stimulatory activity of other DCs that comprise the major fraction of dLN DCs. IDO induction in pDCs depended on inflammatory signaling by means of IFN type I and II receptors, the TLR/IL-1 signaling adaptor MyD88, and on cellular stress responses to amino acid withdrawal by means of the integrated stress response kinase GCN2. Consistent with the hypothesis that T cell suppressive, IDO⁺ pDCs elicited by PMA exposure create local immune privilege that favors tumor development, IDO-deficient mice exhibited a robust tumor-resistant phenotype in the standard DMBA/PMA 2-stage carcinogenesis model of skin papilloma formation. Thus, IDO is a key immunosuppressive factor that facilitates tumor progression in this setting of chronic inflammation driven by repeated topical PMA exposure.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The role of psychological factors influencing chronic pain is well documented, although less is known about the implication and logistics of conducting behavioral and psychological assessments in ...clinical practice, specifically within pain management.
To identify the feasibility and clinical utility of assessing behavioral and psychological risk factors in pain management, as well as documenting the challenges and opportunities of integrating multidisciplinary care into a pain management practice.
A convenience sample of pain management patients was prospectively recruited from a private, multispecialty orthopedic clinic in Tallahassee, Florida. All patients reported experiencing chronic pain (i.e., greater than 3 months).
Patients were approached before their initial clinical interaction at the pain management clinic. Approximately one year following their initial appointment, medical records were reviewed to determine the patients' responses to treatment and subsequent management of their ailments.
Findings from the pilot study suggest that the behavioral and psychological assessments identified much higher rates of depression and suicidal ideations and lower resilience within the sample than in previously published US rates. The median time to complete the consent and battery was 30.2 minutes interquartile range: 21. This suggests that a shortened battery appears feasible in a pain management practice and could offer benefit by identifying factors that are known to impact clinical care.
This study is limited in sample size, restricting generalizability. The incomplete follow-up survey data and cross-sectional nature of the study are also limitations.
The utility and feasibility of psychological and behavioral health assessments appear to be a critical component of a pain management practice as there is substantial overlap with psychological comorbidities (e.g., depression and anxiety) and chronic pain. Positive affect, such as resilience, may act to confer some protection against the sequelae of chronic pain, and identifying such factors appears vital.
BACKGROUND: The role of psychological factors influencing chronic pain has been well documented. This review includes a historical perspective and current examination of the literature on ...psychological and behavioral health characteristics and their influence on chronic pain.
OBJECTIVES: To identify psychological and behavioral health factors involved with chronic pain, as well as the challenges and opportunities of integrating multidisciplinary care into a pain management practice.
STUDY DESIGN: Narrative review of peer-reviewed literature examining psychological and behavioral health factors associated with poor clinical outcomes with an emphasis on orthopedics.
METHODS: The Medline database was reviewed to identify peer-reviewed research that discussed psychological and behavioral health factors relevant to pain management or orthopedics.
RESULTS: The evidence provided suggests that these constructs should receive strong consideration when managing chronic pain. The incorporation of such factors may improve patient care and clinical outcomes and reduce total health care costs.
LIMITATIONS: This narrative review is not systematic in nature, but rather focused on the impacts on orthopedics and pain management.
CONCLUSIONS: Psychological and behavioral health factors should be an integral component of a pain management practice as there is substantial overlap between depression and anxiety with chronic pain. Positive affect, such as resilience, may act as a buffer and confer some protection against the sequelae of chronic pain. There is evidence that psychological screeners offer further insight into the patient condition and would contribute to the treatment plan. The novel role of a behavioral health navigator in a pain management clinic is worthy of further exploration as it has proved beneficial in other chronic health conditions.
KEY WORDS: Pain management, chronic pain, psychological, multidisciplinary, behavioral health navigator, resiliency, opioids
Vertebral compression fractures (VCFs) can be conservatively treated with pain management, bracing, and bed rest, or treated surgically with a kyphoplasty or vertebroplasty procedure.
The objective ...of this retrospective review was to assess the viability, safety, and efficacy of using local anesthesia with oral sedation for an office-based kyphoplasty procedure.
A retrospective review.
Private orthopedic clinic.
Ninety-nine consecutive patients (9 office-based and 90 ambulatory surgical centers ASC) between January 2015 to May 2017 receiving their first percutaneous balloon kyphoplasty (PBK) with our physician in an office-based setting or at an ASC. Clinical outcomes observed were rates of surgical complications, 6-month re-fracture rates, adjacent fracture rates, and postprocedure medical management.
No intraoperative complications were observed during the PBK procedure. No re-fractures occurred during the 6-month follow-up window. A total of 6% of the patients experienced an adjacent vertebral compression fracture, but there were no significant differences between facility type. Level-specific verbal pain score at the postoperative follow-up visit was significantly lower than at the preoperative visit for the cohort (5.3 ± 3.1 vs.7.5 ± 2.0) (P = 0.001) and the ASC group (5.5 ± 3.1 vs. 7.5 ± 2.0) (P = 0.002).
Only 9 single-level office-based PBKs were performed by a single physician andfollowed for at least 6 months suggesting these findings cannot be generalized to all patients, practitioners, facilities, or vertebral augmentation procedures (VAPs).
To the best of our knowledge, this study of a continuous series of primary PBKs was the first to report the safety of an office-based procedure. The cohort reported significantly lower pain at their first postoperative follow-up visit when compared to their preoperative visit, adding to the body of evidence that PBKs are an effective treatment for pain associated with VCFs. The overall adjacent fracture rate in this series (6%) was slightly lower than previously reported for VAPs performed in a hospital under local anesthesia (7%-13%).
Osteoporosis, vertebral compression fracture, kyphoplasty, local anesthesia, office- based, oral sedation.
Foxp3
+ regulatory T (Treg) cells can undergo reprogramming into a phenotype expressing proinflammatory cytokines. However, the biologic significance of this conversion remains unclear. We show that ...large numbers of Treg cells undergo rapid reprogramming into activated T helper cells after vaccination with antigen plus Toll-like receptor 9 (TLR-9) ligand. Helper activity from converted Treg cells proved essential during initial priming of CD8
+ T cells to a new cross-presented antigen. Help from Treg cells was dependent on CD40L, and (unlike help from conventional non-Treg CD4
+ cells) did not require preactivation or prior exposure to antigen. In hosts with established tumors, Treg cell reprogramming was suppressed by tumor-induced indoleamine 2,3-dioxygenase (IDO) and vaccination failed because of lack of help. Treg cell reprogramming, vaccine efficacy, and antitumor CD8
+ T cell responses were restored by pharmacologic inhibition of IDO. Reprogrammed Treg cells can thus participate as previously unrecognized drivers of certain early CD8
+ T cell responses.
► Reprogrammed Treg cells can provide essential help for early CD8
+ T cell responses ► Treg cell reprogramming is suppressed by IDO in tumor-bearing hosts ► Blocking IDO restores Treg cell reprogramming and enhances antitumor vaccine efficacy
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inflammation stimulates immunity but can create immune privilege in some settings. Here, we show that cutaneous Leishmania major infection stimulated expression of the immune regulatory enzyme ...indoleamine 2,3 dioxygenase (IDO) in local lymph nodes. Induced IDO attenuated the T cell stimulatory functions of dendritic cells and suppressed local T cell responses to exogenous and nominal parasite antigens. IDO ablation reduced local inflammation and parasite burdens, as did pharmacologic inhibition of IDO in mice with established infections. IDO ablation also enhanced local expression of proinflammatory cytokines and induced some CD4⁺ T cells to express interleukin (IL) 17. These findings showed that IDO induced by L. major infection attenuated innate and adaptive immune responses. Thus, IDO acts as a molecular switch regulating host responses, and IDO inhibitor drugs are a potential new approach to enhance host immunity to established leishmania infections.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
PDF
