The IL-17 pathway intertwines with neurotrophin and TLR/IL-1R pathways since its domain shuffling origin.

The IL-17 pathway displays remarkably diverse functional modes between different subphyla, classes, and even orders, yet its driving factors remains elusive. Here, we demonstrate that the IL-17 pathway originated through domain shuffling between a Toll-like receptor (TLR)/IL-1R pathway and a neurotrophin-RTK (receptor-tyrosine-kinase) pathway (a Trunk-Torso pathway). Unlike other new pathways that evolve independently, the IL-17 pathway remains intertwined with its donor pathways throughout later evolution. This intertwining not only influenced the gains and losses of domains and components in the pathway but also drove the diversification of the pathway's functional modes among animal lineages. For instance, we reveal that the crustacean female sex hormone, a neurotrophin inducing sex differentiation, could interact with IL-17Rs and thus be classified as true IL-17s. Additionally, the insect prothoracicotropic hormone, a neurotrophin initiating ecdysis in Drosophila by binding to Torso, could bind to IL-17Rs in other insects. Furthermore, IL-17R and TLR/IL-1R pathways maintain crosstalk in amphioxus and zebrafish. Moreover, the loss of the Death domain in the pathway adaptor connection to IκB kinase and stress-activated protein kinase (CIKSs) dramatically reduced their abilities to activate nuclear factor-kappaB (NF-κB) and activator protein 1 (AP-1) in amphioxus and zebrafish. Reinstating this Death domain not only enhanced NF-κB/AP-1 activation but also strengthened anti-bacterial immunity in zebrafish larvae. This could explain why the mammalian IL-17 pathway, whose CIKS also lacks Death, is considered a weak signaling activator, relying on synergies with other pathways. Our findings provide insights into the functional diversity of the IL-17 pathway and unveil evolutionary principles that could govern the pathway and be used to redesign and manipulate it.

Osteosarcoma Cells Secrete CXCL14 That Activates Integrin α11ß1 on Fibroblasts to Form a Lung Metastatic Niche.

Cooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naïve osteosarcoma using single-cell RNA sequencing and identified a stem cell-like cluster with tumor cell-initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell-like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin α11ß1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFß and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11ß1 axis inhibited fibroblast TGFß production, enhanced CD8+ T cell-mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin α11ß1 axis is a potential strategy to inhibit osteosarcoma lung metastasis. SIGNIFICANCE: Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11ß1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.

Mass Spectrometry-Based Proteomics Identifies Serpin B9 as a Key Protein in Promoting Bone Metastases in Lung Cancer.

Bone metastasis (BM) is one of the most common complications of advanced cancer. Immunotherapy for bone metastasis of lung cancer (LCBM) is not so promising and the immune mechanisms are still unknown. Here, we utilized a model of BM by injecting cancer cells through caudal artery (CA) to screen out a highly bone metastatic derivative (LLC1-BM3) from a murine lung cancer cell line LLC1. Mass spectrometry-based proteomics was performed in LLC1-parental and LLC1-BM3 cells. Combining with prognostic survival information from patients with lung cancer, we identified serpin B9 (SB9) as a key factor in BM. Molecular characterization showed that SB9 overexpression was associated with poor prognosis and high bone metastatic burden in lung cancer. Moreover, SB9 could increase the ability of lung cancer cells to metastasize to the bone. The mechanistic studies revealed that tumor-derived SB9 promoted BM through an immune cell-dependent way by inactivating granzyme B, manifesting with the decreased infiltration of cytotoxic T cells and increased expression level of exhausted markers. A specific SB9-targeting inhibitor [1,3-benzoxazole-6-carboxylic acid (BTCA)] significantly suppressed LCBM in the CA mouse model. This study reveals that SB9 may serve as a therapeutic target and potential prognostic marker for patients with LCBM. IMPLICATIONS: SB9 as a therapeutic target for LCBM.

Differential roles of the fish chitinous membrane in gut barrier immunity and digestive compartments.

The chitin-based peritrophic matrix (PM) is a structure critical for both gut immunity and digestion in invertebrates. PM was traditionally considered lost in all vertebrates, but a PM-like chitinous membrane (CM) has recently been discovered in fishes, which may increase the knowledge on vertebrate gut physiology and structural evolution. Here, we show that in zebrafish, the CM affects ingestion behavior, microbial homeostasis, epithelial renewal, digestion, growth, and longevity. Young mutant fish without CM appear healthy and are able to complete their life cycle normally, but with increasing age they develop gut inflammation, resulting in gut atrophy. Unlike mammals, zebrafish have no visible gel-forming mucin layers to protect their gut epithelia, but at least in young fish, the CM is not a prerequisite for the antibacterial gut immunity. These findings provide new insights into the role of the CM in fish prosperity and its eventual loss in tetrapods. These findings may also help to improve fish health and conservation, as well as to advance the understanding of vertebrate gut physiology and human intestinal diseases.

A nanodrug combining CD47 and sonodynamic therapy efficiently inhibits osteosarcoma deterioration.

Treatments for osteosarcoma (OS) with pulmonary metastases reach a bottleneck with a survival rate of 10-20%. The suppressive tumor associated macrophages(TAMs) and CD47 over-expression greatly lead to the treatment failure. Sonodynamic therapy (SDT) can generate ROS with deep tumor penetration to induce tumor cell apoptosis, which is reported to further induce M1 macrophage polarization. CD47 inhibition combined with SDT to synergistically modulate TAMs may induce superior effects for OS treatment. In this work, for the first time, a biomimetic nanodrug named MPIRx was deveploped by loading IR780 (a sonosensitizer) and RRx-001 (a CD47 inhibitor) in PEG-PCL nanomicelles and then coating with OS cell membranes. After ultrasound activation, the nanodrug significantly inhibited OS proliferation and migration, induced apoptosis and immunogenic cell death in OS cells. Furthermore, MPIRx could guide macrophage migrating towards tumor cells and promote M1-type polarization while increasing the phagocytosis activity of macrophages on OS cells. Ultimately, MPIRx showed good tumor accumulation in vivo and successfully inhibited subcutaneous OS and orthotopic tumor with deterioration of pulmonary metastasis. Overall, by creating a local oxidative microenvironment and modulating the TAMs/CD47 in tumor tissue, the MPIRx nanodrug presents a novel strategy for macrophage-related immunotherapy to successfully eliminate OS and inhibit the intractable pulmonary metastasis.

Performing a Safe and Effective Total Hip Arthroplasty on Patients With Inactive or Stably Active Systemic Lupus Erythematosus With Osteonecrosis.

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) are typically treated with total hip arthroplasty (THA) because of osteonecrosis of the femoral head (ONFH). This study evaluated the outcome of THA in this patient group. METHODS: From January 2004 to January 2017, we retrospectively studied 92 THAs for patients with SLE and 92 THAs for age- and sex-matched patients suffering from ONFH due to nonrheumatic etiologies Both groups were treated with cementless THA and followed up for an average of 50.9 ± 30.6 months. Their surgical outcomes and complications were evaluated and compared. RESULTS: No significant difference existed in age, sex, weight, height, follow-up time, and Ficat staging between the groups. All patients with SLE were in inactive or stably active disease conditions. For all patients, the Harris hip score (HHS) (from 52.6 to 92.8; P < 0.001), Physical Component Summary Scale score (PCS) (from 29.4 to 49.3; P < 0.001), and Mmental Component Summary Scale score (MCS) (from 50.5 to 55.5; P < 0.001) of the Short Form-12 improved significantly after surgery. At the final follow-up, the HHS and MCS were comparable between the two groups. The PCS remained lower in the SLE group (P = 0.017), and no recorded revision surgieries in either group. Corticosteroid intake and testing positive for antiphospholipid antibodies, rather than having a SLE disease activity index score greater than zero, were risk factors for higher complications. DISCUSSION: Performing THA for patients with SLE in an inactive or stably active disease condition resulted in comparable postoperative HHS and MCS scores, a lower PCS score, and shorter term postoperative complications compared with patients with ONFH resulting from nonrheumatic diseases. Patients with SLE had a higher risk for postoperative complications. It is generally safe and effective to perform THA in patients with inactive or stably active SLE. However, they still have an increased risk of short-term complications.

Degeneration of three or more lumbar discs significantly decreases lumbar spine/hip ROM ratio during position change from standing to sitting in AVN patients before THA.

BACKGROUND: Limitations in the lumbar spine movement reduce lumbar vertebral motion and affect spinopelvic kinematics. We studied the influence of lumbar intervertebral disc degeneration on spinofemoral movement, from standing to sitting, in patients undergoing total hip arthroplasty (THA). METHODS: Of 138 consecutive patients scheduled for THA due to unilateral avascular necrosis (AVN) of the femoral head, those with ≥3 discs with University of California at Los Angeles (UCLA) disc degeneration score > 1 were defined as the lumbar degenerative disc disease (LDD) group, and the remaining patients constituted d the control group. Full body anteroposterior and lateral EOS images in the standing and sitting positions were obtained. Pelvic incidence (PI), L1 slope (L1 s), lumbar lordosis angle (LL), pelvic tilt (PT), sacral slope (SS), femoral slope (Fs), sagittal vertical axis (SVA), hip flexion, lumbar spine flexion, and total spinofemoral flexion were measured on the images and compared between groups. RESULTS: No significant between-group differences were observed in the height, weight, body mass index, AVN staging, or PI, SS, and Fs on standing. The LDD group included more females and older patients, had 5° lesser LL, 5° greater PT, and larger SVA. From standing to sitting, the PI remained constant in both groups. Total spinofemoral flexion was 7° less, lumbar spine flexion 16° less, L1 slope change 6° less, and SS change 8° less, and hip flexion was 7° more in the LDD than in the control group. The spine/hip flexion ratio was significantly lower in the LDD group (0.3 versus 0.7; p < 0.001). On regression analysis, the LDD group (p < 0.001) and older age (p = 0.048) but not sex, weight, or height were significant univariate predictors of decreased spine/hip ratio. CONCLUSIONS: Patients with LDD leant more forward and had a larger pelvis posterior tilt angle on standing and a decreased lumbar spine/hip flexion ratio, with more hip joint flexion, on sitting, to compensate for reduced lumbar spine flexion. Surgeons should be aware that elderly patients with multiple LDD have significantly different spinofemoral movements and increased risk of posterior dislocation post-THA. Preoperative patient identification, intraoperative surgical technique modification, and individualized rehabilitation protocols are necessary.