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Complement activation is a relevant driver in the pathomechanisms of vasculitis. The involved proteins in the interaction between endothelia, complement, and platelets in these conditions are only partially understood. Thrombospondin-1 (TSP-1), found in platelet α-granules and released from activated endothelial cells, interacts with factor H (FH) and vWF. However, to our knowledge, direct regulatory interaction with the complement cascade has not yet been described. Our study shows that TSP-1 is a potent, FH-independent inhibitor of the alternative complement pathway. TSP-1 binds to complement proteins and inhibits cleavage of C3 and C5 and the formation of the membrane attack complex. We validated complement-regulatory function in blood samples from patients with primary complement defects. The physiological relevance of TSP-1 was demonstrated in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) by significantly enhanced TSP-1 staining in glomerular lesions and increased complement activity and NETosis after TSP-1 deficiency in an in vitro and in vivo model of AAV. The complement-inhibiting function of TSP-1 represents an important mechanism in the interaction of endothelia and complement. In particular, the interplay between released TSP-1 and the complement system locally, especially on surfaces, influences the balance between complement activation and inhibition and may be relevant in various vascular diseases.

Pulmonary hypertension (PH) encompasses a heterogenous group of disorders with the common feature of increased pulmonary arterial pressures. Patients with PH associated with lung disease and/or hypoxia undergo immune-mediated vascular remodeling that includes thickening of the muscular layer surrounding arteries and arterioles. In this issue of the JCI, Kumar and colleagues examined the role of interstitial macrophages in a model of high-altitude PH. Resident interstitial macrophages increased, proliferated, and expressed CCL2, a monocyte chemoattractant ligand. There was also a rise in CCR2 + macrophages expressing thrombospondin-1, which is known to activate vascular remodeling through TGF-β. Blocking monocyte recruitment partially reduced hypoxic PH, and corticosteroid treatment effectively reduced CCL2 expression and CCR2 + monocyte recruitment. Further, plasma samples collected from individuals ascending from low to high altitudes showed increased thrombospondin-1 and TGF-β levels, which were reduced with dexamethasone. These findings reveal interstitial macrophage populations as potential therapeutic targets in hypoxic PH.

Infectious diseases and autoimmunity are leading causes of mortality worldwide. The lack of vaccines and resistance to current treatments by microbes highlight the importance of developing novel therapeutics. Similarly, treatments for autoimmune diseases are limited and require improved approaches. Identifying relevant proteins involved in host defense and tolerance to self-antigens is key to designing novel therapeutic strategies. Thrombospondin-1 (TSP-1) is a host glycoprotein involved in host defense and inflammation. Here, we analyze how TSP-1 interacts with different ligands involved in immunity. Then, we discuss the roles of TSP-1 in infection and autoimmunity to finally examine the therapeutic potential of TSP-1.

Thrombospondin‐1 (TSP1) is generally assumed to suppress the growth of osteosarcoma through inhibiting angiogenesis; however, it is unclear whether TSP1 could affect the antitumor immunity against osteosarcoma. We aimed to explore the immune‐related tumor‐promoting effects of TSP1 and decipher its underlying mechanism. First, we identified that TSP1 regulated programmed death‐ligand 1 (PD‐L1) expression, which was related to the CD8+ T cells anergy in osteosarcoma cells. The exact role of PD‐L1 in the immunosuppressive effect of TSP1 was then further confirmed by the addition of the PD‐L1 neutralizing Ab. With the addition of PD‐L1 neutralizing Abs during cocultivation, the inhibition of CD8+ T cells was abolished to a certain extent. Further mechanistic investigations showed that TSP1‐induced PD‐L1 upregulation was achieved by activation of the signal transducer and activator of transcription 3 (STAT3) pathway. In vivo experiments also indicated that TSP1 overexpression could promote the growth of primary lesions, whereas TSP1 knockdown effectively inhibits the growth of the primary lesion as well as lung metastasis by restoring the antitumor immunity. Thrombospondin‐1 knockdown combined with PD‐L1 neutralizing Ab achieved a more pronounced antitumor effect. Taken together, our study showed that TSP1 upregulates PD‐L1 by activating the STAT3 pathway and, therefore, impairs the antitumor immunity against osteosarcoma. Thrombospondin‐1 (TSP1) can weaken antitumor immunity while promoting angiogenesis, thereby building a microenvironment conducive to osteosarcoma growth. The suppression of immune function by TSP1 can be achieved not only through the traditional mode (TSP1 binding with CD36 or CD47), but also through the programmed death‐ligand 1/programmed death receptor 1 axis. Therefore, TSP1 could be a potential therapeutic target for the treatment of osteosarcoma.

Immune cell infiltration into joint synovial tissue and promotion of the inflammatory response are important processes in rheumatoid arthritis (RA). This article delves into the crucial role of CD47 in these processes, as well as the mechanisms at both cellular and molecular levels. CD47, its ligand TSP-1, and related integrins' expression was analyzed in RA patients' synovial and blood samples vs. normals using GEO data. Additionally, a collagen-induced arthritis (CIA) model using knockout rats was employed to explore the significant role of CD47 in the arthritic process. This was further validated in wild-type rat CIA model using CD47 antibodies and inhibitors targeting key enzymes in the CD47-activated integrin α4β1 signaling pathway. The crucial role of CD47 in the CIA model and its way of function were investigated at the animal whole-body level, through various joint section analyses, and at the cellular and molecular level. Analysis of synovial tissue samples (230 cases) and blood samples (1238 cases) from RA patients in the GEO database showed that the CD47, its ligand TSP-1 and related integrins were significantly overexpressed in RA patients. When was knocked out in a rat CIA model, the disease severity of arthritis was significantly alleviated, and the T cell infiltration into rat synovial tissue was remarkably reduced, while the number of B cells, macrophages, and neutrophils did not noticeably change. Mechanistic studies indicated that CD47 on T cells interacts with TSP-1 on vascular endothelial cells in arthritic synovium, activating T cell integrin α4β1. The activated α4β1 binds to VCAM-1, promoting T cell infiltration and inflammatory factor secretion, thereby exacerbating synovial inflammation. The present study also showed that inhibiting the activities of key kinases PKA and Src, through which CD47 mediated integrin α4β1 activation, alleviated arthritis syndromes in CIA rats. The three-molecule model of \"TSP-1, CD47 and integrin α4β1\" confirmed that CD47 plays an important role in the occurrence and progression of collagen-induced arthritis, a typical animal model of rheumatoid arthritis. Blocking the TSP-1-CD47 interaction or inhibiting CD47-activated integrin α4β1 on T cells could be a potential therapeutic strategy for rheumatoid arthritis.

Pseudomonas aeruginosa pulmonary infection can lead to exaggerated neutrophilic inflammation and tissue destruction, yet host factors that regulate the neutrophilic response is not fully known. IL-36γ is a proinflammatory cytokine that dramatically increases in bioactivity following N-terminal processing by proteases. Interleukin-36γ (IL-36γ), a member of the IL-1 cytokine superfamily, amplifies lung inflammation and impairs host defense during acute pulmonary Pseudomonas aeruginosa infection. To be fully active, IL-36γ is cleaved at its N-terminal region by proteases such as neutrophil elastase (NE) and cathepsin S (CatS). However, it remains unclear whether limiting extracellular proteolysis restrains the inflammatory cascade triggered by IL-36γ during P. aeruginosa infection. Thrombospondin-1 (TSP-1) is a matricellular protein with inhibitory activity against NE and the pathogen-secreted Pseudomonas elastase LasB—both proteases implicated in amplifying inflammation. We hypothesized that TSP-1 tempers the inflammatory response during lung P. aeruginosa infection by inhibiting the proteolytic environment required for IL-36γ activation. Compared to wild-type (WT) mice, TSP-1-deficient (Thbs1 −/− ) mice exhibited a hyperinflammatory response in the lungs during P. aeruginosa infection, with increased cytokine production and an unrestrained extracellular proteolytic environment characterized by higher free NE and LasB, but not CatS activity. LasB cleaved IL-36γ proximally to M 19 at a cleavage site distinct from those generated by NE and CatS, which cleave IL-36γ proximally to Y 16 and S 18 , respectively. N-terminal truncation experiments in silico predicted that the M 19 and the S 18 isoforms bind the IL-36R complex almost identically. IL-36γ neutralization ameliorated the hyperinflammatory response and improved lung immunity in Thbs1 −/− mice during P. aeruginosa infection. Moreover, administration of cleaved IL-36γ induced cytokine production and neutrophil recruitment and activation that was accentuated in Thbs1 −/− mice lungs. Collectively, our data show that TSP-1 regulates lung neutrophilic inflammation and facilitates host defense by restraining the extracellular proteolytic environment required for IL-36γ activation. IMPORTANCE Pseudomonas aeruginosa pulmonary infection can lead to exaggerated neutrophilic inflammation and tissue destruction, yet host factors that regulate the neutrophilic response are not fully known. IL-36γ is a proinflammatory cytokine that dramatically increases in bioactivity following N-terminal processing by proteases. Here, we demonstrate that thrombospondin-1, a host matricellular protein, limits N-terminal processing of IL-36γ by neutrophil elastase and the Pseudomonas aeruginosa -secreted protease LasB. Thrombospondin-1-deficient mice (Thbs1 −/− ) exhibit a hyperinflammatory response following infection. Whereas IL-36γ neutralization reduces inflammatory cytokine production, limits neutrophil activation, and improves host defense in Thbs1 −/− mice, cleaved IL-36γ administration amplifies neutrophilic inflammation in Thbs1 −/− mice. Our findings indicate that thrombospondin-1 guards against feed-forward neutrophilic inflammation mediated by IL-36γ in the lung by restraining the extracellular proteolytic environment.

Inflammation serves as a fundamental defense against tissue injury and infection, yet dysregulation can lead to pathological outcomes. Thrombospondin-1 (Thbs1/TSP1), a multifunctional glycoprotein significantly upregulated during inflammation, exemplifies a dualistic regulator with context-dependent roles. Through modulation of cytokine networks and inflammatory cell activity (notably macrophages), Thbs1 critically governs inflammatory responses. Acute respiratory distress syndrome (ARDS), a life-threatening condition fueled by systemic inflammation secondary to infection or trauma, presents complex pathophysiology requiring elucidation. COVID-19 research highlights elevated Thbs1 expression in severe patients, where it demonstrates protective effects against pulmonary damage primarily via extracellular matrix protection, inhibition of neutrophil serine proteases, and TGF-β-dependent repair pathways. However, paradoxical evidence indicates that dysregulated Thbs1 can also contribute to ARDS pathogenesis, potentially by amplifying inflammation, promoting thromboinflammation, or driving fibrosis. Mechanistic insights reveal Thbs1’s influence on ARDS progression through ECM remodeling, serine protease inhibition, and TGF-β activation. While significant progress has been made in understanding Thbs1 signaling, the precise mechanisms dictating its context-dependent switch between protective and pathogenic functions in inflammatory pathways remain a critical area for future investigation.

Fil: Jaramillo Ortiz, Jose Manuel. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Specific immunotherapy (SIT) is the only specific remedy for the treatment of allergic diseases currently. B cells are important immune cells in the immunity. The role of B cells in immune regulatory activities has not been fully understood yet. This study aims to elucidate the role of the thrombospondin (TSP)1-producing B cells in the immune regulatory role of SIT. The results showed that after SIT, the frequency of CD35 + B cells was increased in the intestine of mice with food allergy. The CD35 + B cells expressed TSP1 after exposure to specific antigens. Co-culture with the TSP1-producing CD35 + B cells decreased the levels of CD80/CD86 in dendritic cells; the cells convert naïve CD4 + T cells to regulatory T cells to inhibit allergic inflammation in the intestine.

The risk of developing lymphoma in patients with Sjögren’s syndrome (SS) is 44 times higher than in the normal population with the most common lymphomas derived from marginal zone B (MZB) cells. Current understanding of the role of MZB cells in SS is primarily based on salivary gland pathology, while their contextual association with lacrimal glands and ocular manifestations largely remains unknown. We examined this possibility using a SS mouse model (thrombospondin-1 deficient (TSP1−/−)) with well-characterized ocular disease. We determined the frequency, localization, and cytokine profiles of MZB cells and their association with an antibody response in TSP1−/− mice treated with a TSP-derived peptide. A significantly increased frequency of MZB cells was detected in the spleens and lacrimal glands of TSP1−/− mice in comparison to wild-type tissues as detected by immunostaining. An altered cytokine profile of TSP1−/− MZB cells was supportive of T helper 17 (Th17)-related pathogenesis. A significantly reduced antibody response and the splenic MZB compartment against an eye-derived antigen were noted in TSP-derived peptide-treated mice. These changes correspond with the previously reported ability of the peptide to ameliorate SS-related ocular manifestations. Collectively, our results demonstrate dysregulation of MZB cells in TSP1−/− mice and highlight their role in the context of SS-related chronic ocular surface disease.