The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review

Background: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) molecule that plays an important role in the repair and regeneration of tissue injury. It also acts as a pro-inflammatory cytokine through the activation of toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), to elicit the neuroinflammatory response. HMGB1 may aggravate several cellular responses which may lead to pathological inflammation and cellular death. Thus, there have been a considerable amount of research into the pathological role of HMGB1 in diseases. However, whether the mechanism of action of HMGB1 is similar in all neurodegenerative disease pathology remains to be determined. Objective: Therefore, this systematic review aimed to critically evaluate and elucidate the role of HMGB1 in the pathology of neurodegeneration based on the available literature. Methods: A comprehensive literature search was performed on four databases; EMBASE, PubMed, Scopus, and CINAHL Plus. Results: A total of 85 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that HMGB1 levels were found elevated in most neurodegeneration except in Huntington’s disease and Spinocerebellar ataxia, where the levels were found decreased. This review also showcased that HMGB1 may act on distinctive pathways to elicit its pathological response leading to the various neurodegeneration processes/diseases. Conclusion: While there have been promising findings in HMGB1 intervention research, further studies may still be required before any HMGB1 intervention may be recommended as a therapeutic target for neurodegenerative diseases.

eNAMPT neutralization reduces preclinical ARDS severity via rectified NFkB and Akt/mTORC2 signaling

Despite encouraging preclinical data, therapies to reduce ARDS mortality remains a globally unmet need, including during the COVID-19 pandemic. We previously identified extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel damage-associated molecular pattern protein (DAMP) via TLR4 ligation which regulates inflammatory cascade activation. eNAMPT is tightly linked to human ARDS by biomarker and genotyping studies in ARDS subjects. We now hypothesize that an eNAMPT-neutralizing mAb will significantly reduce the severity of ARDS lung inflammatory lung injury in diverse preclinical rat and porcine models. Sprague Dawley rats received eNAMPT mAb intravenously following exposure to intratracheal lipopolysaccharide (LPS) or to a traumatic blast (125 kPa) but prior to initiation of ventilator-induced lung injury (VILI) (4 h). Yucatan minipigs received intravenous eNAMPT mAb 2 h after initiation of septic shock and VILI (12 h). Each rat/porcine ARDS/VILI model was strongly associated with evidence of severe inflammatory lung injury with NFkB pathway activation and marked dysregulation of the Akt/mTORC2 signaling pathway. eNAMPT neutralization dramatically reduced inflammatory indices and the severity of lung injury in each rat/porcine ARDS/VILI model (~ 50% reduction) including reduction in serum lactate, and plasma levels of eNAMPT, IL-6, TNFα and Ang-2. The eNAMPT mAb further rectified NFkB pathway activation and preserved the Akt/mTORC2 signaling pathway. These results strongly support targeting the eNAMPT/TLR4 inflammatory pathway as a potential ARDS strategy to reduce inflammatory lung injury and ARDS mortality.

Differential recognition and cytokine induction by the peptidorhamnomannan from Sporothrix brasiliensis and S. schenckii

Sporotrichosis is a deep mycosis caused by dimorphic species of the genus Sporothrix, with differences in pathogenicity between S. schenckii and S. brasiliensis species. Recently, it was discovered that the cell wall peptidorhamnomannan (PRM) of Sporothrix spp . is a pathogen associated molecular pattern (PAMP). Interestingly, S. brasiliensis PRM has additional unknown rhamnose residues. We hypothesize that the structural differences of Sporothrix spp PRMs impact the host's immune response and may explain the severity of sporotrichosis caused by S. brasiliensis. Here we demonstrate that S. brasiliensis yeasts and its PRM (S.b PRM) induced a strong inflammatory response in human PBMCs, with high production of TNF-α, IL-6 and IL-1β and induction of T-helper cytokines IFN-γ, IL-17 and IL-22. In contrast, S. schenckii yeasts and its PRM induced higher concentrations of interleukin-1 receptor antagonist (IL-1Ra), which resulted in low production of T-helper cytokines such as IL-17 and IL-22. CR3 and dectin-1 were required for cytokine induction by both PRMs, while TLR2 and TLR4 were required for the response of S.s PRM and S.b PRM, respectively. IL-1β and IL-1α production induced by S. brasiliensis yeasts and S.b PRM were dependent on inflammasome and caspase-1 activation. S. schenckii and S.s PRM were able to induce IL-1β independent of ROS. In conclusion, these findings improve our understanding of the pathogenesis of Sporothrix spp. by reporting differences of immunological responses induced by S. schenckii and S. brasiliensis. The study also opens the gateway for novel treatment strategies targeting local inflammation and tissue destruction induced by S. brasiliensis infection through IL-1 inhibition.

HMGB1-Mediated Activation of the Inflammatory-Reparative Response Following Myocardial Infarction

Different cell types belonging to the innate and adaptive immune system play mutually non-exclusive roles during the different phases of the inflammatory-reparative response that occurs following myocardial infarction. A timely and finely regulation of their action is fundamental for the process to properly proceed. The high-mobility group box 1 (HMGB1), a highly conserved nuclear protein that in the extracellular space can act as a damage-associated molecular pattern (DAMP) involved in a large variety of different processes, such as inflammation, migration, invasion, proliferation, differentiation, and tissue regeneration, has recently emerged as a possible regulator of the activity of different immune cell types in the distinct phases of the inflammatory reparative process. Moreover, by activating endogenous stem cells, inducing endothelial cells, and by modulating cardiac fibroblast activity, HMGB1 could represent a master regulator of the inflammatory and reparative responses following MI. In this review, we will provide an overview of cellular effectors involved in these processes and how HMGB1 intervenes in regulating each of them. Moreover, we will summarize HMGB1 roles in regulating other cell types that are involved in the different phases of the inflammatory-reparative response, discussing how its redox status could affect its activity.

Emerging Functions of IL-33 in Homeostasis and Immunity

Our understanding of the functions of the IL-1 superfamily cytokine and damage-associated molecular pattern IL-33 continues to evolve with our understanding of homeostasis and immunity. The early findings that IL-33 is a potent driver of type 2 immune responses promoting parasite expulsion, but also inflammatory diseases like allergy and asthma, have been further supported. Yet, as the importance of a type 2 response in tissue repair and homeostasis has emerged, so has the fundamental importance of IL-33 to these processes. In this review, we outline an evolving understanding of IL-33 immunobiology, paying particular attention to how IL-33 directs a network of ST2+ regulatory T cells, reparative and regulatory macrophages, and type 2 innate lymphoid cells that are fundamental to tissue development, homeostasis, and repair. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

New Proteins Contributing to Immune Cell Infiltration and Pannus Formation of Synovial Membrane from Arthritis Diseases

An inflamed synovial membrane plays a major role in joint destruction and is characterized by immune cells infiltration and fibroblast proliferation. This proteomic study considers the inflammatory process at the molecular level by analyzing synovial biopsies presenting a histological inflammatory continuum throughout different arthritis joint diseases. Knee synovial biopsies were obtained from osteoarthritis (OA; n = 9), chronic pyrophosphate arthropathy (CPPA; n = 7) or rheumatoid arthritis (RA; n = 8) patients. The histological inflammatory score was determined using a semi-quantitative scale based on synovial hyperplasia, lymphocytes, plasmocytes, neutrophils and macrophages infiltration. Proteomic analysis was performed by liquid chromatography-mass spectrometry (LC-MS/MS). Differentially expressed proteins were confirmed by immunohistochemistry. Out of the 1871 proteins identified and quantified by LC-MS/MS, 10 proteins (LAP3, MANF, LCP1, CTSZ, PTPRC, DNAJB11, EML4, SCARA5, EIF3K, C1orf123) were differentially expressed in the synovial membrane of at least one of the three disease groups (RA, OA and CPPA). Significant increased expression of the seven first proteins was detected in RA and correlated to the histological inflammatory score. Proteomics is therefore a powerful tool that provides a molecular pattern to the classical histology usually applied for synovitis characterization. Except for LCP1, CTSZ and PTPRC, all proteins have never been described in human synovitis.

Role of Microbiota-Derived Metabolites in Alcoholic and Non-Alcoholic Fatty Liver Diseases

Chronic liver disease encompasses diseases that have various causes, such as alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Gut microbiota dysregulation plays a key role in the pathogenesis of ALD and NAFLD through the gut–liver axis. The gut microbiota consists of various microorganisms that play a role in maintaining the homeostasis of the host and release a wide number of metabolites, including short-chain fatty acids (SCFAs), peptides, and hormones, continually shaping the host’s immunity and metabolism. The integrity of the intestinal mucosal and vascular barriers is crucial to protect liver cells from exposure to harmful metabolites and pathogen-associated molecular pattern molecules. Dysbiosis and increased intestinal permeability may allow the liver to be exposed to abundant harmful metabolites that promote liver inflammation and fibrosis. In this review, we introduce the metabolites and components derived from the gut microbiota and discuss their pathologic effect in the liver alongside recent advances in molecular-based therapeutics and novel mechanistic findings associated with the gut–liver axis in ALD and NAFLD.

Crosstalk between Calcium and ROS Signaling during Flg22-Triggered Immune Response in Arabidopsis Leaves

Calcium and reactive oxygen species (ROS) are two of the earliest second messengers in response to environmental stresses in plants. The rise and sequestration of these messengers in the cytosol and apoplast are formed by various channels, transporters, and enzymes that are required for proper defense responses. It remains unclear how calcium and ROS signals regulate each other during pattern-triggered immunity (PTI). In the present study, we examined the effects of perturbing one signal on the other in Arabidopsis leaves upon the addition of flg22, a well-studied microbe-associated molecular pattern (MAMP). To this end, a variety of pharmacological agents were used to suppress either calcium or ROS signaling. Our data suggest that cytosolic calcium elevation is required to initiate and regulate apoplastic ROS production generated by respiratory burst oxidase homologs (RBOHs). In contrast, ROS has no effect on the initiation of the calcium signal, but is required for forming a sufficient amplitude of the calcium signal. This finding using pharmacological agents is corroborated by the result of using a genetic double mutant, rbohd rbohf. Our study provides an insight into the mutual interplay of calcium and ROS signals during the MAMP-induced PTI response in plants.

Single-cell transcriptomic analysis reveals the critical molecular pattern of UV-induced cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common nonmelanoma skin cancer characterized by high invasiveness, heterogeneity, and mainly occurs in the ultraviolet (UV)-exposed regions of the skin, but its pathogenesis is still unclear. Here, we generated single-cell transcriptome profiles for 350 cells from six primary UV-induced cSCCs, together with matched adjacent skin samples, and three healthy control skin tissues by single-cell RNA-sequencing technology based on Smart-seq2 strategy. A series of bioinformatics analyses and in vitro experiments were used to decipher and validate the critical molecular pattern of cSCC. Results showed that cSCC cells and normal keratinocytes were significantly distinct in gene expression and chromosomal copy number variation. Furthermore, cSCC cells exhibited 18 hallmark pathways of cancer by gene set enrichment analysis. Differential expression analysis demonstrated that many members belonging to S100 gene family, SPRR gene family, and FABP5 were significantly upregulated in cSCC cells. Further experiments confirmed their upregulation and showed that S100A9 or FABP5 knockdown in cSCC cells inhibited their proliferation and migration through NF-κB pathway. Taken together, our data provide a valuable resource for deciphering the molecular pattern in UV-induced cSCC at a single-cell level and suggest that S100A9 and FABP5 may provide novel targets for therapeutic intervention of cSCC in the future.

Role of RAGE and Its Ligands on Inflammatory Responses to Brain Tumors

Gliomas, the most common form of brain cancer, can range from relatively slow-growing low-grade to highly aggressive glioblastoma that has a median overall survival of only 15 months despite multimodal standard therapy. Although immunotherapy with checkpoint inhibitors has significantly improved patient survival for some cancers, to date, these agents have not shown consistent efficacy against malignant gliomas. Therefore, there is a pressing need to better understand the impact of host inflammatory responses on the efficacy of emerging immunotherapy approaches for these resistant tumors. RAGE is a multi-ligand pattern recognition receptor that is activated in various inflammatory states such as diabetes, Alzheimer’s disease, cystic fibrosis, and cancer. Low levels of RAGE can be found under normal physiological conditions in neurons, immune cells, activated endothelial, and vascular smooth muscle cells, but it is over-expressed under chronic inflammation due to the accumulation of its ligands. RAGE binds to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA which mediate downstream cellular responses that promote tumor growth, angiogenesis, and invasion. Both in vitro and in vivo studies have shown that inhibition of RAGE signaling can disrupt inflammation and cancer progression and metastasis. Here, we will review our current understanding of the role of RAGE pathway on glioma progression and how it could be exploited to improve the efficacy of immunotherapy approaches.