von Willebrand factor (VWF) is a peculiar protein not only by being the largest protein that travels through our vessels or by the way hemodynamic forces regulate its platelet-binding functions but also because of its pleiotropic influence on a diverse spectrum of physiological and pathological processes. In addition to the well-established mechanisms by which VWF supports primary hemostasis and functions as a chaperone-protein for coagulation factor VIII, we are now beginning to understand in more detail how VWF exerts its activities beyond hemostasis. For instance, the various ways by which VWF may modulate angiogenic processes has been elucidated during the last decade [1Starke R.D. Ferraro F. Paschalaki K.E. Dryden N.H. McKinnon T.A. Sutton R.E. Payne E.M. Haskard D.O. Hughes A.D. Cutler D.F. Laffan M.A. Randi A.M. Endothelial von Willebrand factor regulates angiogenesis.Blood. 2011; 117: 1071-1080Crossref PubMed Scopus (342) Google Scholar, 2Randi A.M. Smith K.E. Castaman G. von Willebrand factor regulation of blood vessel formation.Blood. 2018; 132: 132-140Crossref PubMed Scopus (95) Google Scholar, 3de Vries M.R. Peters E.A.B. Quax P.H.A. Nossent A.Y. von Willebrand factor deficiency leads to impaired blood flow recovery after ischaemia in mice.Thromb Haemost. 2017; 117: 1412-1419Crossref PubMed Scopus (11) Google Scholar]. More recently, it has been shown that VWF promotes smooth muscle cell proliferation via direct interactions with the LRP4-αVβ3 receptor complex, thereby inducing signaling pathways that include p38MAP kinase activation [[4]Lagrange J. Worou M.E. Michel J.B. Raoul A. Didelot M. Muczynski V. Legendre P. Plénat F. Gauchotte G. Lourenco-Rodrigues M.D. Christophe O.D. Lenting P.J. Lacolley P. Denis C.V. Regnault V. The VWF/LRP4/αVβ3-axis represents a novel pathway regulating proliferation of human vascular smooth muscle cells.Cardiovasc Res. 2022; 118: 622-637Crossref PubMed Scopus (5) Google Scholar]. Drakeford et al. [[5]Drakeford C. Aguila S. Roche F. Hokamp K. Fazavana J. Cervantes M.P. Curtis A.M. Hawerkamp H.C. Dhami S.P.S. Charles-Messance H. Hackett E.E. Chion A. Ward S. Ahmad A. Schoen I. Breen E. Keane J. Murphy R. Preston R.J.S. O’Sullivan J.M. et al.von Willebrand factor links primary hemostasis to innate immunity.Nat Commun. 2022; 13: 6320Crossref PubMed Scopus (1) Google Scholar] recently reported a new breakthrough in our understanding of VWF function beyond hemostasis (ie, its role in innate immunity). Ample evidence that VWF contributes to inflammatory responses has been reviewed by Kawecki et al. [[6]Kawecki C. Lenting P.J. Denis C.V. von Willebrand factor and inflammation.J Thromb Haemost. 2017; 15: 1285-1294Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar]. VWF is able to recruit leukocytes to sites of inflammation via direct interactions and via the formation of platelet strings that enable platelet-leukocyte interactions [7Pendu R. Terraube V. Christophe O.D. Gahmberg C.G. de Groot P.G. Lenting P.J. Denis C.V. P-selectin glycoprotein ligand 1 and beta2-integrins cooperate in the adhesion of leukocytes to von Willebrand factor.Blood. 2006; 108: 3746-3752Crossref PubMed Scopus (130) Google Scholar, 8Lerolle N. Dunois-Lardé C. Badirou I. Motto D.G. Hill G. Bruneval P. Diehl J.L. Denis C.V. Baruch D. von Willebrand factor is a major determinant of ADAMTS-13 decrease during mouse sepsis induced by cecum ligation and puncture.J Thromb Haemost. 2009; 7: 843-850Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 9Petri B. Broermann A. Li H. Khandoga A.G. Zarbock A. Krombach F. Goerge T. Schneider S.W. Jones C. Nieswandt B. Wild M.K. Vestweber D. von Willebrand factor promotes leukocyte extravasation.Blood. 2010; 116: 4712-4719Crossref PubMed Scopus (149) Google Scholar, 10Hillgruber C. Steingräber A.K. Pöppelmann B. Denis C.V. Ware J. Vestweber D. Nieswandt B. Schneider S.W. Goerge T. Blocking von Willebrand factor for treatment of cutaneous inflammation.J Invest Dermatol. 2014; 134: 77-86Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 11Adam F. Casari C. Prévost N. Kauskot A. Loubière C. Legendre P. Repérant C. Baruch D. Rosa J.P. Bryckaert M. de Groot P.G. Christophe O.D. Lenting P.J. Denis C.V. A genetically-engineered von Willebrand disease type 2B mouse model displays defects in hemostasis and inflammation.Sci Rep. 2016; 626306Crossref Scopus (15) Google Scholar, 12Aymé G. Adam F. Legendre P. Bazaa A. Proulle V. Denis C.V. Christophe O.D. Lenting P.J. A novel single-domain antibody against von Willebrand factor A1 domain resolves leukocyte recruitment and vascular leakage during inflammation-brief report.Arterioscler Thromb Vasc Biol. 2017; 37: 1736-1740Crossref PubMed Scopus (26) Google Scholar]. However, little was known about the interaction between VWF and another player in the immune system: the macrophage. In the context of VWF biology, macrophages are mainly known as cells that are part of the catabolic pathway that eliminates VWF from circulation [[13]van Schooten C.J. Shahbazi S. Groot E. Oortwijn B.D. van den Berg H.M. Denis C.V. Lenting P.J. Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo.Blood. 2008; 112: 1704-1712Crossref PubMed Scopus (117) Google Scholar,[14]Chion A. O’Sullivan J.M. Drakeford C. Bergsson G. Dalton N. Aguila S. Ward S. Fallon P.G. Brophy T.M. Preston R.J.S. Brady L. Sheils O. Laffan M. McKinnon T.A.J. O’Donnell J.S. N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance.Blood. 2016; 128: 1959-1968Crossref PubMed Scopus (26) Google Scholar]. In addition, VWF located at the surface of liver macrophages (Kupffer cells) plays a role in the surveillance mechanism that is designed to eliminate platelet/bacteria complexes from circulation [[15]Wong C.H. Jenne C.N. Petri B. Chrobok N.L. Kubes P. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance.Nat Immunol. 2013; 14: 785-792Crossref PubMed Scopus (252) Google Scholar]. Drakeford et al. [[5]Drakeford C. Aguila S. Roche F. Hokamp K. Fazavana J. Cervantes M.P. Curtis A.M. Hawerkamp H.C. Dhami S.P.S. Charles-Messance H. Hackett E.E. Chion A. Ward S. Ahmad A. Schoen I. Breen E. Keane J. Murphy R. Preston R.J.S. O’Sullivan J.M. et al.von Willebrand factor links primary hemostasis to innate immunity.Nat Commun. 2022; 13: 6320Crossref PubMed Scopus (1) Google Scholar] now show that VWF has the potential to drive macrophages into a proinflammatory M1 phenotype. In a series of elegant experiments, Drakeford et al. [[5]Drakeford C. Aguila S. Roche F. Hokamp K. Fazavana J. Cervantes M.P. Curtis A.M. Hawerkamp H.C. Dhami S.P.S. Charles-Messance H. Hackett E.E. Chion A. Ward S. Ahmad A. Schoen I. Breen E. Keane J. Murphy R. Preston R.J.S. O’Sullivan J.M. et al.von Willebrand factor links primary hemostasis to innate immunity.Nat Commun. 2022; 13: 6320Crossref PubMed Scopus (1) Google Scholar] demonstrated that VWF binding to macrophages (either THP-1–derived or blood-borne monocyte–derived) induces p38MAP kinase signaling, forcing a change in gene expression pattern, with 1334 genes displaying modified expression (Figure). Notably, proinflammatory cytokines and chemokines were upregulated, and increased production of tumor necrosis factor, interleukin (IL)-6, IL-1β, chemokine C-C ligand (CCL)-2, CCL-3, and CCL-4 was detected. Interestingly, the supernatant of VWF-stimulated macrophages appeared more efficient in recruiting naïve monocytes compared with the supernatant of lipopolysaccharide-stimulated macrophages, illustrating the proinflammatory potential of the VWF/macrophage axis. Perhaps unexpectedly, VWF induced changes not only in the expression of genes associated with the inflammatory response but also of those involved in metabolic pathways (Figure). These alterations provoked a marked increase in glycolytic activity in combination with changes in the morphology of mitochondria. High glycolytic activity is indeed known to modify the structure of mitochondria and is characteristic of the inflammatory phenotype of macrophages [[16]O’Neill L.A. Kishton R.J. Rathmell J. A guide to immunometabolism for immunologists.Nat Rev Immunol. 2016; 16: 553-565Crossref PubMed Scopus (1458) Google Scholar]. An important finding during their studies was that VWF-induced macrophage reprogramming is transient, in contrast to changes induced by lipopolysaccharides, which proved long-lasting (Figure). Knowing that VWF is one of the so-called acute-phase proteins, it seems possible that transient increases in VWF levels (for instance, in response to endothelial stimulation) allow for a temporary, reversible stimulation of macrophages toward the proinflammatory M1 phenotype. This temporary effect may originate from the notion that VWF is efficiently endocytosed and degraded by macrophages. To identify the receptor that mediates the VWF-induced alterations in the gene expression profile and subsequent phenotype of the macrophages, the authors turned to receptors that were previously identified to be involved in the catabolism of VWF. One of these receptors is the scavenger receptor low-density lipoprotein (LDL)-receptor related protein-1 (LRP1) [[17]Rastegarlari G. Pegon J.N. Casari C. Odouard S. Navarrete A.M. Saint-Lu N. van Vlijmen B.J. Legendre P. Christophe O.D. Denis C.V. Lenting P.J. Macrophage LRP1 contributes to the clearance of von Willebrand factor.Blood. 2012; 119: 2126-2134Crossref PubMed Scopus (88) Google Scholar]. By using dedicated inhibitors of LRP1 (ie, anti-LRP1 antibodies and the universal LDL-receptor related protein–inhibitor Receptor-Associated Protein), the authors were able to partially neutralize the proinflammatory effect of VWF. Signaling via the p38MAP kinase pathway was approximately halved, and consequently, macrophages were less willing to turn into the M1 phenotype. This strongly suggests that LRP1 not only is indeed involved in the endocytosis of VWF but also is a key element in VWF-dependent reprogramming of the macrophages. It should be noted that the role of the VWF-LRP1 interaction is perhaps more complex than one would think at first sight. Previous studies have shown that LRP1 can induce both pro- and anti-inflammatory outcomes, as illustrated by the findings that a loss of macrophage LRP1 has a dual and opposite effect on atherosclerotic plaque biogenesis, depending on whether the plaque is growing or shrinking [[18]Overton C.D. Yancey P.G. Major A.S. Linton M.F. Fazio S. Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse.Circ Res. 2007; 100: 670-677Crossref PubMed Scopus (117) Google Scholar,[19]Mueller P.A. Zhu L. Tavori H. Huynh K. Giunzioni I. Stafford J.M. Linton M.F. Fazio S. Deletion of macrophage low-density lipoprotein receptor-related protein 1 (LRP1) accelerates atherosclerosis regression and increases C-C chemokine receptor type 7 (CCR7) expression in plaque macrophages.Circulation. 2018; 138: 1850-1863Crossref PubMed Scopus (57) Google Scholar]. Is it possible that different LRP1-mediated signals into the macrophage are dependent on the ligand that binds to LRP1? In favor of this would be the finding that factor VIII (also a ligand for LRP1) does not modify the phenotype of macrophages [[20]Kis-Toth K. Rajani G.M. Simpson A. Henry K.L. Dumont J. Peters R.T. Salas J. Loh C. Recombinant factor VIII Fc fusion protein drives regulatory macrophage polarization.Blood Adv. 2018; 2: 2904-2916Crossref PubMed Scopus (15) Google Scholar]. Another possibility is that the multimeric nature of VWF allows for oligomerization of LRP1 receptors at the cellular surface, a condition that perhaps could force LRP1-mediated signaling into the proinflammatory direction. Moreover, another option is that there is another yet unidentified receptor involved. LRP1 (and other members of the LDL-receptor related protein family) is known to form heterologous-receptor complexes at the surface of cells, and it is not uncommon that this is done in a cell-specific manner. Examples of these are complexes of LRP1 and the NMDA receptor on neuronal cells, LRP1 and the receptor tyrosine kinase EphA2 on glioblastoma cells, and LRP1 with the PDGF receptor on smooth muscle cells [21May P. Rohlmann A. Bock H.H. Zurhove K. Marth J.D. Schomburg E.D. Noebels J.L. Beffert U. Sweatt J.D. Weeber E.J. Herz J. Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice.Mol Cell Biol. 2004; 24: 8872-8883Crossref PubMed Scopus (165) Google Scholar, 22Gopal U. Bohonowych J.E. Lema-Tome C. Liu A. Garrett-Mayer E. Wang B. Isaacs J.S. A novel extracellular Hsp90 mediated co-receptor function for LRP1 regulates EphA2 dependent glioblastoma cell invasion.PLoS One. 2011; 6e17649Crossref Scopus (102) Google Scholar, 23Boucher P. Gotthardt M. Li W.P. Anderson R.G. Herz J. LRP: role in vascular wall integrity and protection from atherosclerosis.Science. 2003; 300: 329-332Crossref PubMed Scopus (467) Google Scholar]. Of particular interest in this regard is the capacity of LRP1 to form complexes with β2-integrins at the surface of leukocytes, knowing that these integrins (notably αDβ2) are associated with a proinflammatory phenotype of macrophages [[24]Spijkers P.P.E.M. da Costa Martins P. Westein E. Gahmberg C.G. Zwaginga J.J. Lenting P.J. LDL-receptor-related protein regulates beta2-integrin-mediated leukocyte adhesion.Blood. 2005; 105: 170-177Crossref PubMed Scopus (42) Google Scholar,[25]Aziz M.H. Cui K. Das M. Brown K.E. Ardell C.L. Febbraio M. Pluskota E. Han J. Wu H. Ballantyne C.M. Smith J.D. Cathcart M.K. Yakubenko V.P. The upregulation of integrin αDβ2 (CD11d/CD18) on inflammatory macrophages promotes macrophage retention in vascular lesions and development of atherosclerosis.J Immunol. 2017; 198: 4855-4867Crossref PubMed Scopus (36) Google Scholar]. Moreover, β2-integrins are similar to LRP1 in that they can bind to VWF, suggesting that a tertiary complex can be formed between VWF, LRP1, and β2-integrins [[7]Pendu R. Terraube V. Christophe O.D. Gahmberg C.G. de Groot P.G. Lenting P.J. Denis C.V. P-selectin glycoprotein ligand 1 and beta2-integrins cooperate in the adhesion of leukocytes to von Willebrand factor.Blood. 2006; 108: 3746-3752Crossref PubMed Scopus (130) Google Scholar]. It would be of interest to investigate whether the formation of this tertiary complex is responsible for the proinflammatory reprogramming of macrophages. The in vivo relevance of the VWF-macrophage axis was tested in a mouse model of chemotaxis. After peritoneal deposition of VWF, the cellular content of the peritoneum was analyzed at 3 and 24 hours. No differences were observed between vehicle- and VWF-treated mice after 3 hours. In contrast, after 24 hours, VWF-treated mice were characterized by an increased number of small peritoneal macrophages, a population of macrophages that is known to expand in response to inflammatory stimuli (Figure). Macrophages isolated from the peritoneum also manifested increased expression of proinflammatory cytokines, such as tumor necrosis factor, IL-6, and IL-1β. Having identified VWF as a proinflammatory agent, the next question is obviously how this would affect us in daily life. As mentioned earlier in the article, the link between VWF and inflammation has been fairly well established in different animal models, including stroke and atherosclerosis. This association is perhaps less clear in the human context, because it is less easy to investigate given that confounding variables are often present. However, having more insight into the molecular basis on which VWF exerts its proinflammatory activity may help us to further define the conditions in which VWF plays a more or less relevant role in the inflammatory response. In particular, the interplay between lung macrophages and VWF in conditions such as systemic inflammatory response syndrome (SIRS) and COVID-19 could be of interest. VWF levels are markedly increased in COVID-19, whereas SIRS is characterized by increased levels of active VWF (a platelet-binding conformation that also promotes binding to LRP1) [[17]Rastegarlari G. Pegon J.N. Casari C. Odouard S. Navarrete A.M. Saint-Lu N. van Vlijmen B.J. Legendre P. Christophe O.D. Denis C.V. Lenting P.J. Macrophage LRP1 contributes to the clearance of von Willebrand factor.Blood. 2012; 119: 2126-2134Crossref PubMed Scopus (88) Google Scholar,26Fogarty H. Ward S.E. Townsend L. Karampini E. Elliott S. Conlon N. Dunne J. Kiersey R. Naughton A. Gardiner M. Byrne M. Bergin C. O’Sullivan J.M. Martin-Loeches I. Nadarajan P. Bannan C. Mallon P.W. Curley G.F. Preston R.J.S. Rehill A.M. et al.Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction.J Thromb Haemost. 2022; 20: 2429-2438Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 27Rauch A. Labreuche J. Lassalle F. Goutay J. Caplan M. Charbonnier L. Rohn A. Jeanpierre E. Dupont A. Duhamel A. Faure K. Lambert M. Kipnis E. Garrigue 4, Delphine Lenting 8, Peter J. Poissy 9, Julien Susen Sophie Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19.J Thromb Haemost. 2020; 18: 2942-2953Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 28Hyseni A. Kemperman H. de Lange D.W. Kesecioglu J. de Groot P.G. Roest M. Active von Willebrand factor predicts 28-day mortality in patients with systemic inflammatory response syndrome.Blood. 2014; 123: 2153-2156Crossref PubMed Scopus (34) Google Scholar]. Moreover, increased levels of VWF in COVID-19 or active VWF in SIRS are associated with exaggerated inflammatory responses and an increased risk of mortality [[28]Hyseni A. Kemperman H. de Lange D.W. Kesecioglu J. de Groot P.G. Roest M. Active von Willebrand factor predicts 28-day mortality in patients with systemic inflammatory response syndrome.Blood. 2014; 123: 2153-2156Crossref PubMed Scopus (34) Google Scholar,[29]Philippe A. Gendron N. Bory O. Beauvais A. Mirault T. Planquette B. Sanchez O. Diehl J.L. Chocron R. Smadja D.M. Von Willebrand factor collagen-binding capacity predicts in-hospital mortality in COVID-19 patients: insight from VWF/ADAMTS13 ratio imbalance.Angiogenesis. 2021; 24: 407-411Crossref PubMed Scopus (15) Google Scholar]. These findings may provide a rationale for studies aiming to reduce plasma levels of VWF or to interfere with VWF-LRP1 interactions to limit the inflammatory response under such conditions. The other side of the coin would be conditions in which VWF is deficient or dysfunctional, as in von Willebrand disease. The difficulty here is that von Willebrand disease is a very heterogenous disease, both from a molecular and clinical point of view. It will be complicated to design studies to explore the connection between VWF and innate immunity in such a heterogenous group of patients, especially if these patients receive prophylactic treatment with VWF concentrates. However, the availability of large national health care databases may open new avenues to explore this intriguing relationship in more detail. In conclusion, Drakeford et al. [[5]Drakeford C. Aguila S. Roche F. Hokamp K. Fazavana J. Cervantes M.P. Curtis A.M. Hawerkamp H.C. Dhami S.P.S. Charles-Messance H. Hackett E.E. Chion A. Ward S. Ahmad A. Schoen I. Breen E. Keane J. Murphy R. Preston R.J.S. O’Sullivan J.M. et al.von Willebrand factor links primary hemostasis to innate immunity.Nat Commun. 2022; 13: 6320Crossref PubMed Scopus (1) Google Scholar] have presented an elegant study that further confirms the multifunctional role of VWF beyond hemostasis. Having identified (at least in part) the molecular pathways that contribute to the proinflammatory action of VWF toward macrophages, this knowledge will help us to better understand the complex relationship between hemostasis and innate immunity. All authors contributed to the writing and editing of the manuscript. There are no competing interests to disclose.