Targeting the Pentraxin 3/CD44 Axis: A Potential Treatment for Pulmonary Fibrosis

Pulmonary fibrosis is characterized by progressive scarring of the lung parenchyma surrounding the alveoli that leads to respiratory failure and ultimately death. The idiopathic form of pulmonary fibrosis (or IPF), while rare in incidence, affects over 100,000 people in the US alone, and 30,000–40,000 new cases arise worldwide every year.1 Prognosis for IPF remains poor with a median survival of less than 5 years after initial diagnosis. Currently there is no cure, although, pharmacologic treatments (Pirfenidone/Nintedanib) have been shown to slow down disease progression by blocking myofibroblast activation, collagen synthesis and the transforming growth factor-beta (TGF-β) pathway.2 TGF-β signaling is well documented to serve a central role in mediating fibrogenesis; however, TGF-β is critical in biological development and specifically targeting this pathway may lead to undesirable consequences. In addition, IPF has multiple etiologies; therefore, developing therapeutic targets has remained a challenge (Figure 1). Some non- pharmacologic approaches have focused on cellular therapy, or mesenchymal stem cell (MSC) infusion, as a treatment to regulate lung injury and repair,3 but current and approved treatment strategies are mainly symptomatic and include oxygen therapy, exercise for pulmonary rehabilitation, and lung transplantation.2 Aging factors such as fibroblast growth factor 23 (FGF23) and its co-receptor/anti-aging hormone, klotho (KL), have also been suggested as possible targets to promote anti-fibrotic and anti-inflammatory responses.4 Pharmacologic approaches, on the other hand, have focused on inhibiting pro-fibrotic mediators, one of which is galectin-3, a beta-galactoside binding protein that interacts with multiple growth factor receptors to activate profibrotic signaling pathways. TD139 (currently known as GB0139), a small molecule galectin-3 inhibitor, was shown to be safe and well tolerated in IPF subjects, who showed improvements in plasma biomarkers of inflammation.5 In addition, pharmacologic approaches focusing on pentraxin supplementation have also been reported in IPF. PTX2, a member of the PTX superfamily, has been targeted as a novel therapeutic option to treat IPF. PTX2 has been shown to modulate wound healing and fibrotic remodeling of injured tissue through binding to cellular debris, enhancing phagocytosis by leukocytes, and inhibiting the production of TGF-β.6 PRM-151 (Zinpentraxin Alfa), a recombinant human PTX2 protein, has been proposed for pharmacologic treatment of treat IPF and is currently in a phase 3 trial with an estimated completion date of March 2023. In the Journal of Clinical and Translational Medicine, Chi et al. evaluated the pentraxin 3 (PTX3)/CD44 axis as an effective strategy to treat lung injury-induced fibrosis. PTX3 is an acute phase protein that participates in resistance against inflammation and microorganisms. CD44 is a transmembrane receptor that interacts with various ligands and growth factor receptors to facilitate cellular processes. They note that PTX3 is a novel biomarker of inflammation and elevated serum PTX3 levels are associated with extracellular matrix (ECM) formation thus providing the impetus for their present study. The authors show that PTX3 binding to its receptor, CD44, activates downstream signaling pathways NF-κB, PI3K/AKT, and MAPKs promoting lung fibroblast-mediated fibrogenesis. Blocking PTX3 and CD44 interaction in vivo and in vitro was suggested to effectively reduce myofibroblast activation, ECM formation, and an overall reduction in lung injury. Compared to the current treatment regimen, such as pirfenidone and nintedanib, their αPTX3i treatment showed similar effectiveness in lung injury resolution, pulmonary function, and overall survival in their in vivo experiments. These findings suggest that PTX3/CD44 may be a potential option for fibrosis resolution. However, the role of PTX3/CD44 in fibrogenesis and/or how its blockade contributes to resolution still remain unclear. It is known that PTX3 is produced by a wide variety of cell types and the PTX3/CD44 axis has been explored in other diseases. In influenza infection, PTX3 responds to pro-inflammatory stimuli and binds to a variety of viral strains to mediate host anti-viral responses.7 In cancer, PTX3 antibodies and synthetic peptides can disrupt the PTX3/CD44 interaction and attenuate/restrict the stemness and metastasis/invasion of tripe-negative breast cancers.8 These studies detail the importance of the PTX3/CD44 axis and its contribution to a wide array of inflammatory- and non-inflammatory-mediated processes, which may impact fibrosis and fibrosis resolution. Does PTX3/CD44 blockade, which leads to fibrosis resolution in animal models, translate to humans? Are there limitations to the pre-clinical models used? Bleomycin-induced pulmonary fibrosis in young mice has been shown to resolve over time whereas a non-resolving aged mouse or a repetitive bleomycin instillation model would better recapitulate human pulmonary fibrosis.9, 10 What are the side-effects of PTX3/CD44 blockade? As stated above, PTX3 is produced in multiple cell types, and blockade may cause unwarranted side effects. PTX3 is also involved in the innate immunity response, and blocking its function may lead to immune-wide complications. Is there a connection between PTX2 and PTX3 in IPF? PTX2 is downregulated in IPF, but PTX3 is upregulated; therefore, both have differing therapeutic intervention strategies. PTX2 therapy centers on intravenous infusion of exogenous proteins to delay fibrosis whereas Chi et al. focuses on blocking PTX3 function to prevent or resolve fibrosis. Overall, Chi et al. characterize PTX3 as a novel and attractive target for anti-fibrotic therapy and its underlying mechanism, but more studies are needed to understand the role of the PTX3/CD44 axis in prevention and resolution of pulmonary fibrosis as well as its potential as a therapeutic target in IPF. The authors declare no conflict of interest.