CD8+ T cells reduce neuroretina inflammation in mouse by regulating autoreactive Th1 and Th17 cells through IFN-γ.

Various regulatory CD8+ T-cell subsets have been proposed for immune tolerance and have been implicated in controlling autoimmune diseases. However, their phenotypic identities and suppression mechanisms are not yet understood. This study found that coculture of T-cell receptor (TCR)- or interferon (IFN)-ß-activated CD8+ T cells significantly suppressed the cytokine production of Th1 and Th17 cells. By experimenting with the experimental autoimmune uveitis (EAU), we found that adoptive transfer of TCR or IFN-ß-activated CD8+ T cells significantly lessened disease development in an IFN-γ-dependent manner with a decreased uveitogenic Th1 and Th17 response. Interestingly, after adoptive transfer into the EAU mice, the IFN-γ+ CD8+ T cells were recruited more efficiently into the secondary lymphoid organs during the disease-priming phase. This recruitment depends on the IFN-γ-inducible chemokine receptor CXCR3; knocking out CXCR3 abolishes the protective effect of CD8+ T cells in EAU. In conclusion, we identified the critical role of IFN-γ for CD8+ T cells to inhibit Th1 and Th17 responses and ameliorate EAU. CXCR3 is necessary to recruit IFN-γ+ CD8+ T cells to the secondary lymphoid organ for the regulation of autoreactive Th1 and Th17 cells.

Regulatory T cell intravitreal delivery using hyaluronan methylcellulose hydrogel improves therapeutic efficacy in experimental autoimmune uveitis.

Autoimmune uveitis refers to several intraocular inflammation conditions, which are mediated by autoreactive T cells. Regulatory T cells (Tregs) are immunosuppressive cells that have shown potential for resolving various autoimmune diseases, including uveitis. However, poor donor cell dispersion distal to the injection site and plasticity of Treg cells in an inflammatory microenvironment can present obstacles for this immunotherapy. We assessed the use of a physical blend of hyaluronan and methylcellulose (HAMC) as immunoprotective and injectable hydrogel cell delivery system to improve the efficacy of Treg-based therapy in treating experimental autoimmune uveitis (EAU). We demonstrated that the Treg-HAMC blend increased both the survival and stability of Tregs under proinflammatory conditions. Furthermore, we found that the intravitreal HAMC delivery system resulted in a two-fold increase in the number of transferred Tregs in the inflamed eye of EAU mice. Treg-HAMC delivery effectively attenuated ocular inflammation and preserved the visual function of EAU mice. It significantly decreased the number of ocular infiltrates, including the uveitogenic IFN-γ+CD4+ and IL-17+CD4+ T cells. In contrast, intravitreal injection of Treg cells without HAMC only achieved marginal therapeutic effects in EAU. Our findings suggest that HAMC may become a promising delivery vehicle for human uveitis Treg therapy.

Multifunctional Interleukin-24 Resolves Neuroretina Autoimmunity via Diverse Mechanisms.

IL-24 is a multifunctional cytokine that regulates both immune cells and epithelial cells. Although its elevation is associated with a number of autoimmune diseases, its tolerogenic properties against autoreactive T cells have recently been revealed in an animal model of central nervous system (CNS) autoimmunity by inhibiting the pathogenic Th17 response. To explore the potential of IL-24 as a therapeutic agent in CNS autoimmunity, we induced experimental autoimmune uveitis (EAU) in wildtype mice and intravitreally injected IL-24 into the inflamed eye after disease onset. We found that the progression of ocular inflammation was significantly inhibited in the IL-24-treated eye when compared to the control eye. More importantly, IL-24 treatment suppressed cytokine production from ocular-infiltrating, pathogenic Th1 and Th17 cells. In vitro experiments confirmed that IL-24 suppressed both Th1 and Th17 differentiation by regulating their master transcription factors T-bet and RORγt, respectively. In addition, we found that intravitreal injection of IL-24 suppressed the production of proinflammatory cytokines and chemokines from the retinas of the EAU-inflamed eyes. This observation appears to be applicable in humans, as IL-24 similarly inhibits human retinal pigment epithelium cells ARPE-19. In conclusion, we report here that IL-24, as a multifunctional cytokine, is capable of resolving ocular inflammation in EAU mice by targeting both uveitogenic T cells and RPE cells. This study sheds new light on IL-24 as a potential therapeutic candidate for autoimmune uveitis.

Injectable chitosan hydrogels tailored with antibacterial and antioxidant dual functions for regenerative wound healing.

Herein, an injectable self-healing hydrogel with inherent antibacterial activity was fabricated based on the dynamic covalent bond formation between boronic acid and catechol groups in quaternized chitosan as building blocks in conjunct with the in-situ encapsulation of epigallocatechin-3-gallate (EGCG, a green tea derivative). Benefiting from the catechol groups and therapeutic effect of EGCG, the resulting natural-based injectable hydrogels showed excellent antibacterial and antioxidant dual functions in preventing bacterial infection and scavenging radicals. The hydrogels loaded with EGCG also exhibited good biocompatibility along with contact-active antibacterial activity via a "capture and kill" strategy. The dynamic covalent bonding enables shear-thinning delivery of the gels via syringe, followed by rapid self-healing. Additionally, the in vivo wound healing evaluation in a full-thickness skin defect model revealed the appreciable and regenerative wound healing performance of the hydrogels, demonstrating their great potential as novel wound dressings for wound management.

Degradable polyprodrugs: design and therapeutic efficiency.

Prodrugs are developed to increase the therapeutic properties of drugs and reduce their side effects. Polyprodrugs emerged as highly efficient prodrugs produced by the polymerization of one or several drug monomers. Polyprodrugs can be gradually degraded to release therapeutic agents. The complete degradation of polyprodrugs is an important factor to guarantee the successful disposal of the drug delivery system from the body. The degradation of polyprodrugs and release rate of the drugs can be controlled by the type of covalent bonds linking the monomer drug units in the polymer structure. Therefore, various types of polyprodrugs have been developed based on polyesters, polyanhydrides, polycarbonates, polyurethanes, polyamides, polyketals, polymetallodrugs, polyphosphazenes, and polyimines. Furthermore, the presence of stimuli-responsive groups, such as redox-responsive linkages (disulfide, boronate ester, metal-complex, and oxalate), pH-responsive linkages (ester, imine, hydrazone, acetal, orthoester, P-O and P-N), light-responsive (metal-complex, o-nitrophenyl groups) and enzyme-responsive linkages (ester, peptides) allow for a selective degradation of the polymer backbone in targeted tumors. We envision that new strategies providing a more efficient synergistic therapy will be developed by combining polyprodrugs with gene delivery segments and targeting moieties.

Interleukin-24 Immunobiology and Its Roles in Inflammatory Diseases.

Interleukin (IL)-24 belongs to the IL-10 family and signals through two receptor complexes, i.e., IL-20RA/IL-20RB and IL-20RB/IL22RA1. It is a multifunctional cytokine that can regulate immune response, tissue homeostasis, host defense, and oncogenesis. Elevation of IL-24 is associated with chronic inflammation and autoimmune diseases, such as psoriasis, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). Its pathogenicity has been confirmed by inducing inflammation and immune cell infiltration for tissue damage. However, recent studies also revealed their suppressive functions in regulating immune cells, including T cells, B cells, natural killer (NK) cells, and macrophages. The tolerogenic properties of IL-24 were reported in various animal models of autoimmune diseases, suggesting the complex functions of IL-24 in regulating autoimmunity. In this review, we discuss the immunoregulatory functions of IL-24 and its roles in autoimmune diseases.

Functionalized Masks: Powerful Materials against COVID-19 and Future Pandemics.

The outbreak of COVID-19 revealed the vulnerability of commercially available face masks. Without having antibacterial/antiviral activities, the current masks act only as filtering materials of the aerosols containing microorganisms. Meanwhile, in surgical masks, the viral and bacterial filtration highly depends on the electrostatic charges of masks. These electrostatic charges disappear after 8 h, which leads to a significant decline in filtration efficiency. Therefore, to enhance the masks' protection performance, fabrication of innovative masks with more advanced functions is in urgent demand. This review summarizes the various functionalizing agents which can endow four important functions in the masks including i) boosting the antimicrobial and self-disinfectant characteristics via incorporating metal nanoparticles or photosensitizers, ii) increasing the self-cleaning by inserting superhydrophobic materials such as graphenes and alkyl silanes, iii) creating photo/electrothermal properties by forming graphene and metal thin films within the masks, and iv) incorporating triboelectric nanogenerators among the friction layers of masks to stabilize the electrostatic charges and facilitating the recharging of masks. The strategies for creating these properties toward the functionalized masks are discussed in detail. The effectiveness and limitation of each method in generating the desired properties are well-explained along with addressing the prospects for the future development of masks.

Induction of antigen-specific Treg cells in treating autoimmune uveitis via bystander suppressive pathways without compromising anti-tumor immunity.

BACKGROUND: Induction of autoantigen-specific Treg cells that suppress tissue-specific autoimmunity without compromising beneficial immune responses is the holy-grail for immunotherapy to autoimmune diseases. METHODS: In a model of experimental autoimmune uveitis (EAU) that mimics human uveitis, ocular inflammation was induced by immunization with retinal antigen interphotoreceptor retinoid-binding protein (IRBP). Mice were given intraperitoneal injection of αCD4 antibody (Ab) after the onset of disease, followed by administration of IRBP. EAU was evaluated clinically and functionally. Splenocytes, CD4+CD25- and CD4+CD25+ T cells were sorted and cultured with IRBP or αCD3 Ab. T cell proliferation and cytokine production were assessed. FINDINGS: The experimental approach resulted in remission of ocular inflammation and rescue of visual function in mice with established EAU. Mechanistically, the therapeutic effect was mediated by induction of antigen-specific Treg cells that inhibited IRBP-driven Th17 response in TGF-ß and IL-10 dependent fashion. Importantly, the Ab-mediated immune tolerance could be achieved in EAU mice by administration of retinal autoantigens, arrestin but not limited to IRBP only, in an antigen-nonspecific bystander manner. Further, these EAU-suppressed tolerized mice did not compromise their anti-tumor T immunity in melanoma model. INTERPRETATION: We successfully addressed a specific immunotherapy of EAU by in vivo induction of autoantigen-specific Treg cells without compromising host overall T cell immunity, which should have potential implication for patients with autoimmune uveitis. FUNDING: This study was supported by the Natural Science Foundation of Guangdong Province and the Fundamental Research Fund of the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center.

Deficiency of IL-27 Signaling Exacerbates Experimental Autoimmune Uveitis with Elevated Uveitogenic Th1 and Th17 Responses.

Human uveitis is an autoimmune disease of the central nervous system that is characterized by ocular inflammation with the involvement of uveitogenic Th1 and Th17 responses. In experimental autoimmune uveitis (EAU), the animal model for human uveitis, both responses are proven to be critical in disease development. Therefore, targeting both Th1 and Th17 cells has therapeutic implication for disease resolution. IL-27 is a multifunctional cytokine that can either promote or inhibit T cell responses and is implicated in both autoimmune and infectious diseases. The aim of this study is to characterize the role of IL-27/IL-27R signaling in regulating uveitogenic Th1/Th17 responses in EAU. By immunizing IL-27Rα-/- mice and their wild-type (WT) littermates for EAU, we demonstrated that IL-27 signaling deficiency exacerbated EAU with severe ocular inflammation and impairment of visual function. Furthermore, there was a significant increase in the eye-infiltrating Th1 and Th17 cells in IL-27Rα-/- EAU mice compared to WT. Their retinal antigen-specific Th1 and Th17 responses were also significantly increased, as represented by the elevation of their signature cytokines, IFN-γ and IL-17A, respectively. We also observed the upregulation of another pathogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), from effector T cells in IL-27Rα-/- EAU mice. Mechanistic studies confirmed that IL-27 inhibited GM-CSF production from Th17 cells. In addition, the induction of IL-10 producing type 1 regulatory T (Tr1) cells was impaired in IL-27Rα-/- EAU mice. These results identified that IL-27 signaling plays a suppressive role in EAU by regulating multiple CD4+ cell subsets, including the effector Th1 and Th17 cells and the regulatory Tr1 cells. Our findings provide new insights for therapeutic potential in controlling uveitis by enhancing IL-27 signaling.

Antimicrobial/Biocompatible Hydrogels Dual-Reinforced by Cellulose as Ultrastretchable and Rapid Self-Healing Wound Dressing.

Hydrogels as a wound dressing, integrated with ultrastretchability, rapid self-healing, and excellent antimicrobial activity, are in high demand, particularly for joint skin wound healing. Herein, a multifunctional and ductile composite hydrogel was developed using poly(vinyl alcohol) (PVA)-borax gel as a matrix that was synergized or dual-reinforced with dopamine-grafted oxidized carboxymethyl cellulose (OCMC-DA) and cellulose nanofibers (CNF). Moreover, neomycin (NEO), an aminoglycoside antibiotic with multifunctional groups, was incorporated into the hydrogel network as both an antibacterial agent and a cross-linker. The dynamic reversible borate ester linkages and hydrogen bonds between OCMC-DA, PVA, and CNF, along with dynamic cross-linking imine linkages between NEO and OCMC-DA, endowed the hydrogel with excellent self-healing ability and stretchability (3300%). The as-reinforced networks enhanced the mechanical properties of hydrogels significantly. More remarkably, the composite hydrogel with improved biodegradability and biocompatibility is pH-responsive and effective against a broad spectrum of bacteria, which is attributed to the controllable release of NEO for steady availability of the antibiotic on the wound location. Overall, the antimicrobial hydrogel with rapid self-healing and reliable mechanical properties holds significant promise as dressing material for wound healing.

Natural Polymer-Based Antimicrobial Hydrogels without Synthetic Antibiotics as Wound Dressings.

Wound healing is usually accompanied by bacterial infection. The excessive use of synthetic antibiotics leads to drug resistance, posing a significant threat to human health. Hydrogel-based wound dressings aimed at mitigating bacterial infections have emerged as an effective wound treatment. The review presented herein particularly focuses on the hydrogels originating from natural polymers. To further enhance the performance of wound dressings, various strategies and approaches have been developed to endow the hydrogels with excellent broad-spectrum antibacterial activity. Those that are summarized in the current review are the hydrogels with intrinsic or stimuli-triggered bactericidal properties and others that serve as vehicles for loading antibacterial agents without synthetic antibiotics. Specific attention is paid to antimicrobial mechanisms and the antibacterial performance of hydrogels. Practical antibacterial applications to accelerate the wound healing employing these antibiotic-free hydrogels are also introduced along with the discussion on the current challenges and perspectives leading to new technologies.

The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24.

Dysregulated Th17 cell responses underlie multiple inflammatory and autoimmune diseases, including autoimmune uveitis and its animal model, EAU. However, clinical trials targeting IL-17A in uveitis were not successful. Here, we report that Th17 cells were regulated by their own signature cytokine, IL-17A. Loss of IL-17A in autopathogenic Th17 cells did not reduce their pathogenicity and instead elevated their expression of the Th17 cytokines GM-CSF and IL-17F. Mechanistic in vitro studies revealed a Th17 cell-intrinsic autocrine loop triggered by binding of IL-17A to its receptor, leading to activation of the transcription factor NF-κB and induction of IL-24, which repressed the Th17 cytokine program. In vivo, IL-24 treatment ameliorated Th17-induced EAU, whereas silencing of IL-24 in Th17 cells enhanced disease. This regulatory pathway also operated in human Th17 cells. Thus, IL-17A limits pathogenicity of Th17 cells by inducing IL-24. These findings may explain the disappointing therapeutic effect of targeting IL-17A in uveitis.