Matrix Biology最新文献

{"title":"The role of fibrosis in cardiomyopathies: An opportunity to develop novel biomarkers of disease activity","authors":"Elisavet Angeli ,&nbsp;Maria Jordan ,&nbsp;Mandy Otto ,&nbsp;Stevan D. Stojanović ,&nbsp;Morten Karsdal ,&nbsp;Johann Bauersachs ,&nbsp;Thomas Thum ,&nbsp;Jan Fiedler ,&nbsp;Federica Genovese","doi":"10.1016/j.matbio.2024.02.008","DOIUrl":"10.1016/j.matbio.2024.02.008","url":null,"abstract":"<div><p>Cardiomyopathies encompass a spectrum of heart disorders with diverse causes and presentations. Fibrosis stands out as a shared hallmark among various cardiomyopathies, reflecting a common thread in their pathogenesis. This prevalent fibrotic response is intricately linked to the consequences of dysregulated extracellular matrix (ECM) remodeling, emphasizing its significance in the development and progression the disease. This review explores the ECM involvement in various cardiomyopathies and its impact on myocardial stiffness and fibrosis. Additionally, we discuss the potential of ECM fragments as early diagnosis, prognosis, and risk stratification. Biomarkers deriving from turnover of collagens and other ECM proteins hold promise in clinical applications. We outline current clinical management, future directions, and the potential for personalized ECM-targeted therapies with specific focus on microRNAs. In summary, this review examines the role of the fibrosis in cardiomyopathies, highlighting the potential of ECM-derived biomarkers in improving disease management with implications for precision medicine.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"128 ","pages":"Pages 65-78"},"PeriodicalIF":6.9,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139998106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of positional information in determining dermal fibroblast diversity","authors":"Pratyusha Chitturi,&nbsp;Andrew Leask","doi":"10.1016/j.matbio.2024.02.009","DOIUrl":"10.1016/j.matbio.2024.02.009","url":null,"abstract":"<div><p>The largest mammalian organ, skin, consisting of a dermal connective tissue layer that underlies and supports the epidermis, acts as a protective barrier that excludes external pathogens and disseminates sensory signals emanating from the local microenvironment. Dermal connective tissue is comprised of a collagen-rich extracellular matrix (ECM) that is produced by connective tissue fibroblasts resident within the dermis. When wounded, a tissue repair program is induced whereby fibroblasts, in response to alterations in the microenvironment, produce new ECM components, resulting in the formation of a scar. Failure to terminate the normal tissue repair program causes fibrotic conditions including: hypertrophic scars, keloids, and the systemic autoimmune connective tissue disease scleroderma (systemic sclerosis, SSc). Histological and single-cell RNA sequencing (scRNAseq) studies have revealed that fibroblasts are heterogeneous and highly plastic. Understanding how this diversity contributes to dermal homeostasis, wounding, fibrosis, and cancer may ultimately result in novel anti-fibrotic therapies and personalized medicine. This review summarizes studies supporting this concept.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"128 ","pages":"Pages 31-38"},"PeriodicalIF":6.9,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000362/pdfft?md5=39f70e589c6770fd750b2ae39b89e2e3&pid=1-s2.0-S0945053X24000362-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139998107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microvascular damage, neuroinflammation and extracellular matrix remodeling in Col18a1 knockout mice as a model for early cerebral small vessel disease","authors":"Mahsima Khoshneviszadeh ,&nbsp;Solveig Henneicke ,&nbsp;Daniel Pirici ,&nbsp;Akilashree Senthilnathan ,&nbsp;Lorena Morton ,&nbsp;Philipp Arndt ,&nbsp;Rahul Kaushik ,&nbsp;Oula Norman ,&nbsp;Jari Jukkola ,&nbsp;Ildiko Rita Dunay ,&nbsp;Constanze Seidenbecher ,&nbsp;Anne Heikkinen ,&nbsp;Stefanie Schreiber ,&nbsp;Alexander Dityatev","doi":"10.1016/j.matbio.2024.02.007","DOIUrl":"10.1016/j.matbio.2024.02.007","url":null,"abstract":"<div><p>Collagen type XVIII (COL18) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of COL18 would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old <em>Col18a1^−/−</em> mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed brain-wide in capillaries and arterioles. BBB permeability increased with age and affected cortical regions and the hippocampus in 12-month-old <em>Col18a1^−/−</em> mice. None of the <em>Col18a1^−/−</em> mice displayed hallmarks of advanced CSVD, such as hemorrhages, and did not show perivascular space enlargement. <em>Col18a1</em> deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. We verified the pivotal role of COL18 for small vessel wall structure in CSVD by demonstrating the protein's involvement in vascular remodeling in autopsy brains from patients with cerebral hypertensive arteriopathy. Our study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"128 ","pages":"Pages 39-64"},"PeriodicalIF":6.9,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X2400026X/pdfft?md5=f5e54f1667086f5aee9e56f6e36957f1&pid=1-s2.0-S0945053X2400026X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139917019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A lysyl oxidase-responsive collagen peptide illuminates collagen remodeling in wound healing","authors":"Paul Hiebert ,&nbsp;Giuseppe Antoniazzi ,&nbsp;Matthew Aronoff ,&nbsp;Sabine Werner ,&nbsp;Helma Wennemers","doi":"10.1016/j.matbio.2024.02.006","DOIUrl":"10.1016/j.matbio.2024.02.006","url":null,"abstract":"<div><p>Tissue repair and fibrosis involve the dynamic remodeling of collagen, and accurate detection of these sites is of utmost importance. Here, we use a collagen peptide sensor (<strong>1</strong>) to visualize collagen formation and remodeling during wound healing in mice and humans. We show that the probe binds selectively to sites of collagen formation and remodeling at different stages of healing. Compared to conventional methods, the peptide sensor localizes preferentially to areas of collagen synthesis and remodeling at the wound edge and not in matured fibrillar collagen. We also demonstrate its applicability for <em>in vivo</em> wound imaging and for discerning differential remodeling in wounds of transgenic mice with altered collagen dynamics. Our findings show the value of <strong>1</strong> as a diagnostic tool to rapidly identify the sites of matrix remodeling in tissue sections, which will aid in the conception of new therapeutic strategies for fibrotic disorders and defective tissue repair.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"128 ","pages":"Pages 11-20"},"PeriodicalIF":6.9,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000258/pdfft?md5=9c7f01eb15a3e7eb570c79764f015938&pid=1-s2.0-S0945053X24000258-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139916920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The adhesion GPCR and PCP component flamingo (FMI-1) alters body size and regulates the composition of the extracellular matrix","authors":"Johanna Lena Schön ,&nbsp;Victoria Elisabeth Groß ,&nbsp;Willem Berend Post ,&nbsp;Alexandra Daum ,&nbsp;Daniel Matúš ,&nbsp;Johanna Pilz ,&nbsp;Rene Schnorr ,&nbsp;Susanne Horn ,&nbsp;Miriam Bäumers ,&nbsp;Stefanie Weidtkamp-Peters ,&nbsp;Samantha Hughes ,&nbsp;Torsten Schöneberg ,&nbsp;Simone Prömel","doi":"10.1016/j.matbio.2024.02.005","DOIUrl":"10.1016/j.matbio.2024.02.005","url":null,"abstract":"<div><p>The extracellular matrix (ECM) is a network of macromolecules that presents a vital scaffold for cells and enables multiple ways of cellular communication. Thus, it is essential for many physiological processes such as development, tissue morphogenesis, homeostasis, the shape and partially the size of the body and its organs. To ensure these, the composition of the ECM is tissue-specific and highly dynamic. ECM homeostasis is therefore tightly controlled by several mechanisms.</p><p>Here, we show that FMI-1, the homolog of the Adhesion GPCR Flamingo/CELSR/ADGRC in the nematode <em>Caenorhabditis elegans</em>, modulates the composition of the ECM by controlling the production both of ECM molecules such as collagens and also of ECM modifying enzymes. Thereby, FMI-1 affects the morphology and functionality of the nematode´s cuticle, which is mainly composed of ECM, and also modulates the body size. Mechanistic analyses highlight the fact that FMI-1 exerts its function from neurons non-cell autonomously (<em>trans</em>) solely via its extracellular N terminus. Our data support a model, by which the activity of the receptor, which has a well-described role in the planar cell polarity (PCP) pathway, involves the PCP molecule VANG-1, but seems to be independent of the DBL-1/BMP pathway.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"128 ","pages":"Pages 1-10"},"PeriodicalIF":6.9,"publicationDate":"2024-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000246/pdfft?md5=a8bd278d8e87c1f01e376f3063d345f1&pid=1-s2.0-S0945053X24000246-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysfunctional latent transforming growth factor β activation after corneal injury in a classical Ehlers–Danlos model","authors":"Mei Sun ,&nbsp;Ana Carolina Acosta ,&nbsp;Victoria Emerick ,&nbsp;Sheila Adams ,&nbsp;Marcel Y Avila ,&nbsp;Curtis E Margo ,&nbsp;Edgar M Espana","doi":"10.1016/j.matbio.2024.02.004","DOIUrl":"10.1016/j.matbio.2024.02.004","url":null,"abstract":"<div><p>Patients with classical Ehlers Danlos syndrome (cEDS) suffer impaired wound healing and from scars formed after injuries that are atrophic and difficult to close surgically. Haploinsufficiency in COL5A1 creates systemic morphological and functional alterations in the entire body. We investigated mechanisms that impair wound healing from corneal lacerations (full thickness injuries) in a mouse model of cEDS (<em>Col5a1</em>^+/−). We found that collagen V reexpression in this model is upregulated during corneal tissue repair and that wound healing is delayed, impaired, and results in large atrophic corneal scars. We noted that in a matrix with a 50 % content of collagen V, activation of latent Transforming Growth Factor (TGF) β is dysregulated. Corneal myofibroblasts with a haploinsufficiency of collagen V failed to mechanically activate latent TGF β. Second harmonic imaging microscopy showed a disorganized, undulated, and denser collagen matrix in our <em>Col5a1</em>^+/- model that suggested alterations in the extracellular matrix structure and function. We hypothesize that a regenerated collagen matrix with only 50 % content of collagen V is not resistant enough mechanically to allow adequate activation of latent TGF β by fibroblasts and myofibroblasts.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"128 ","pages":"Pages 21-30"},"PeriodicalIF":6.9,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139716562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Keratinocyte integrin α3β1 induces expression of the macrophage stimulating factor, CSF-1, through a YAP/TEAD-dependent mechanism.","authors":"Whitney M. Longmate ,&nbsp;Emily Norton ,&nbsp;Giesse Albeche Duarte ,&nbsp;Lei Wu ,&nbsp;Mathieu R. DiPersio ,&nbsp;John M. Lamar ,&nbsp;C. Michael DiPersio","doi":"10.1016/j.matbio.2024.02.003","DOIUrl":"10.1016/j.matbio.2024.02.003","url":null,"abstract":"<div><p>The development of wound therapy targeting integrins is hampered by inadequate understanding of integrin function in cutaneous wound healing and the wound microenvironment. Following cutaneous injury, keratinocytes migrate to restore the skin barrier, and macrophages aid in debris clearance. Thus, both keratinocytes and macrophages are critical to the coordination of tissue repair. Keratinocyte integrins have been shown to participate in this coordinated effort by regulating secreted factors, some of which crosstalk to distinct cells in the wound microenvironment. Epidermal integrin α3β1 is a receptor for laminin-332 in the cutaneous basement membrane. Here we show that wounds deficient in epidermal α3β1 express less epidermal-derived macrophage colony-stimulating factor 1 (CSF-1), the primary macrophage-stimulating growth factor. α3β1-deficient wounds also have fewer wound-proximal macrophages, suggesting that keratinocyte α3β1 may stimulate wound macrophages through the regulation of CSF-1. Indeed, using a set of immortalized keratinocytes, we demonstrate that keratinocyte-derived CSF-1 supports macrophage growth, and that α3β1 regulates <em>Csf1</em> expression through Src-dependent stimulation of Yes-associated protein (YAP)-Transcriptional enhanced associate domain (TEAD)-mediated transcription. Consistently, α3β1-deficient wounds <em>in vivo</em> display a substantially reduced number of keratinocytes with YAP-positive nuclei. Overall, our current findings identify a novel role for epidermal integrin α3β1 in regulating the cutaneous wound microenvironment by mediating paracrine crosstalk from keratinocytes to wound macrophages, implicating α3β1 as a potential target of wound therapy.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"127 ","pages":"Pages 48-56"},"PeriodicalIF":6.9,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139716563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kidney resident macrophages have distinct subsets and multifunctional roles","authors":"Christine Chew ,&nbsp;Oliver J Brand ,&nbsp;Tomohiko Yamamura ,&nbsp;Craig Lawless ,&nbsp;Mychel Raony Paiva Teixeira Morais ,&nbsp;Leo Zeef ,&nbsp;I-Hsuan Lin ,&nbsp;Gareth Howell ,&nbsp;Sylvia Lui ,&nbsp;Franziska Lausecker ,&nbsp;Christopher Jagger ,&nbsp;Tovah N Shaw ,&nbsp;Siddharth Krishnan ,&nbsp;Flora A McClure ,&nbsp;Hayley Bridgeman ,&nbsp;Kelly Wemyss ,&nbsp;Joanne E Konkel ,&nbsp;Tracy Hussell ,&nbsp;Rachel Lennon","doi":"10.1016/j.matbio.2024.02.002","DOIUrl":"10.1016/j.matbio.2024.02.002","url":null,"abstract":"<div><h3>Background</h3><p>The kidney contains distinct glomerular and tubulointerstitial compartments with diverse cell types and extracellular matrix components. The role of immune cells in glomerular environment is crucial for dampening inflammation and maintaining homeostasis. Macrophages are innate immune cells that are influenced by their tissue microenvironment. However, the multifunctional role of kidney macrophages remains unclear.</p></div><div><h3>Methods</h3><p>Flow and imaging cytometry were used to determine the relative expression of CD81 and CX₃CR1 (C-X3-C motif chemokine receptor 1) in kidney macrophages. Monocyte replenishment was assessed in <em>Cx3cr1</em>^CreER X <em>R26-yfp</em>-reporter and shielded chimeric mice. Bulk RNA-sequencing and mass spectrometry-based proteomics were performed on isolated kidney macrophages from wild type and <em>Col4a5</em>^−/− (Alport) mice. RNAscope was used to visualize transcripts and macrophage purity in bulk RNA assessed by CIBERSORTx analyses.</p></div><div><h3>Results</h3><p>In wild type mice we identified three distinct kidney macrophage subsets using CD81 and CX₃CR1 and these subsets showed dependence on monocyte replenishment. In addition to their immune function, bulk RNA-sequencing of macrophages showed enrichment of biological processes associated with extracellular matrix. Proteomics identified collagen IV and laminins in kidney macrophages from wild type mice whilst other extracellular matrix proteins including cathepsins, ANXA2 and LAMP2 were enriched in <em>Col4a5^−/−</em> (Alport) mice. A subset of kidney macrophages co-expressed matrix and macrophage transcripts.</p></div><div><h3>Conclusions</h3><p>We identified CD81 and CX₃CR1 positive kidney macrophage subsets with distinct dependence for monocyte replenishment. Multiomic analysis demonstrated that these cells have diverse functions that underscore the importance of macrophages in kidney health and disease.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"127 ","pages":"Pages 23-37"},"PeriodicalIF":6.9,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000210/pdfft?md5=07a30ae5fc61894613edbbab00b8f6ca&pid=1-s2.0-S0945053X24000210-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139708384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel muscle-derived extracellular matrix hydrogel promotes angiogenesis and neurogenesis in volumetric muscle loss","authors":"Zhuoyue Chen ,&nbsp;Yaqing Huang ,&nbsp;Hao Xing ,&nbsp;Tiffany Tseng ,&nbsp;Hailey Edelman ,&nbsp;Rachel Perry ,&nbsp;Themis R. Kyriakides","doi":"10.1016/j.matbio.2024.02.001","DOIUrl":"10.1016/j.matbio.2024.02.001","url":null,"abstract":"<div><p>Volumetric muscle loss (VML) represents a clinical challenge due to the limited regenerative capacity of skeletal muscle. Most often, it results in scar tissue formation and loss of function, which cannot be prevented by current therapies. Decellularized extracellular matrix (DEM) has emerged as a native biomaterial for the enhancement of tissue repair. Here, we report the generation and characterization of hydrogels derived from DEM prepared from WT or thrombospondin (TSP)-2 null muscle tissue. TSP2-null hydrogels, when compared to WT, displayed altered architecture, protein composition, and biomechanical properties and allowed enhanced invasion of C2C12 myocytes and chord formation by endothelial cells. They also displayed enhanced cell invasion, innervation, and angiogenesis following subcutaneous implantation. To evaluate their regenerative capacity, WT or TSP2 null hydrogels were used to treat VML injury to tibialis anterior muscles and the latter induced greater recruitment of repair cells, innervation, and blood vessel formation and reduced inflammation. Taken together, these observations indicate that TSP2-null hydrogels enhance angiogenesis and promote muscle repair in a VML model.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"127 ","pages":"Pages 38-47"},"PeriodicalIF":6.9,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139690506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inter-alpha-trypsin inhibitor (IαI) and hyaluronan modifications enhance the innate immune response to influenza virus in the lung","authors":"Fengying Tang ,&nbsp;Stephen R. Reeves ,&nbsp;Jourdan E. Brune ,&nbsp;Mary Y. Chang ,&nbsp;Christina K. Chan ,&nbsp;Peter Waldron ,&nbsp;Sheona P. Drummond ,&nbsp;Caroline M. Milner ,&nbsp;Kimberly M. Alonge ,&nbsp;Stavros Garantziotis ,&nbsp;Anthony J. Day ,&nbsp;William A. Altemeier ,&nbsp;Charles W. Frevert","doi":"10.1016/j.matbio.2024.01.004","DOIUrl":"10.1016/j.matbio.2024.01.004","url":null,"abstract":"&lt;div&gt;&lt;p&gt;The inter-alpha-trypsin inhibitor (IαI) complex is composed of the bikunin core protein with a single chondroitin sulfate (CS) attached and one or two heavy chains (HCs) covalently linked to the CS chain. The HCs from IαI can be transferred to hyaluronan (HA) through a TNFα-stimulated gene-6 (TSG-6) dependent process to form an HC•HA matrix. Previous studies reported increased IαI, HA, and HC•HA complexes in mouse bronchoalveolar lavage fluid (BALF) post-influenza infection. However, the expression and incorporation of HCs into the HA matrix of the lungs during the clinical course of influenza A virus (IAV) infection and the biological significance of the HC•HA matrix are poorly understood. The present study aimed to better understand the composition of HC•HA matrices in mice infected with IAV and how these matrices regulate the host pulmonary immune response. In IAV infected mice bikunin, HC1–3, TSG-6, and HAS1–3 all show increased gene expression at various times during a 12-day clinical course. The increased accumulation of IαI and HA was confirmed in the lungs of infected mice using immunohistochemistry and quantitative digital pathology. Western blots confirmed increases in the IαI components in BALF and lung tissue at 6 days post-infection (dpi). Interestingly, HCs and bikunin recovered from BALF and plasma from mice 6 dpi with IAV, displayed differences in the HC composition by Western blot analysis and differences in bikunin's CS chain sulfation patterns by mass spectrometry analysis. This strongly suggests that the IαI components were synthesized in the lungs rather than translocated from the vascular compartment. HA was significantly increased in BALF at 6 dpi, and the HA recovered in BALF and lung tissues were modified with HCs indicating the presence of an HC•HA matrix. &lt;em&gt;In vitro&lt;/em&gt; experiments using polyinosinic-polycytidylic acid (poly(I:C)) treated mouse lung fibroblasts (MLF) showed that modification of HA with HCs increased cell-associated HA, and that this increase was due to the retention of HA in the MLF glycocalyx. &lt;em&gt;In vitro&lt;/em&gt; studies of leukocyte adhesion showed differential binding of lymphoid (Hut78), monocyte (U937), and neutrophil (dHL60) cell lines to HA and HC•HA matrices. Hut78 cells adhered to immobilized HA in a size and concentration-dependent manner. In contrast, the binding of dHL60 and U937 cells depended on generating a HC•HA matrix by MLF. Our &lt;em&gt;in vivo&lt;/em&gt; findings, using multiple bronchoalveolar lavages, correlated with our &lt;em&gt;in vitro&lt;/em&gt; findings in that lymphoid cells bound more tightly to the HA-glycocalyx in the lungs of influenza-infected mice than neutrophils and mononuclear phagocytes (MNPs). The neutrophils and MNPs were associated with a HC•HA matrix and were more readily lavaged from the lungs. In conclusion, this work shows increased IαI and HA accumulation and the formation of a HC•HA matrix in mouse lungs post-IAV infection. The formation of HA and HC•HA matrices could p","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"126 ","pages":"Pages 25-42"},"PeriodicalIF":6.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139474576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}