PTX3 Regulation of Inflammation, Hemostatic Response, Tissue Repair, and Resolution of Fibrosis Favors a Role in Limiting Idiopathic Pulmonary Fibrosis

Andrea Doni,Remo Castro Russo,Barbara Bottazzi,Alberto Mantovani

doi:10.3389/fimmu.2021.676702

Abstract

PTX3 is a soluble pattern recognition molecule (PRM) belonging to the humoral innate immune system, rapidly produced at inflammatory sites by phagocytes and stromal cells in response to infection or tissue injury. PTX3 interacts with microbial moieties and selected pathogens, with molecules of the complement and hemostatic systems, and with extracellular matrix (ECM) components. In wound sites, PTX3 interacts with fibrin and plasminogen and favors a timely removal of fibrin-rich ECM for an efficient tissue repair. Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown origin, associated with excessive ECM deposition affecting tissue architecture, with irreversible loss of lung function and impact on the patient’s life quality. Maccarinelli et al. recently demonstrated a protective role of PTX3 using the bleomycin (BLM)-induced experimental model of lung fibrosis, in line with the reported role of PTX3 in tissue repair. However, the mechanisms and therapeutic potential of PTX3 in IPF remained to be investigated. Herein, we provide new insights on the possible role of PTX3 in the development of IPF and BLM-induced lung fibrosis. In mice, PTX3-deficiency was associated with worsening of the disease and with impaired fibrin removal and subsequently increased collagen deposition. In IPF patients, microarray data indicated a down-regulation of PTX3 expression, thus suggesting a potential rational underlying the development of disease. Therefore, we provide new insights for considering PTX3 as a possible target molecule underlying therapeutic intervention in IPF.

Highlights

Role of PTX3 in Humoral Innate ImmunityThe pentraxin family is an ancient group of evolutionarily conserved proteins belonging to humoral innate immunity that act as pattern recognition molecules (PRM)
Results reported by Maccarinelli and colleagues and our observations indicate a protective and regulatory role of PTX3 in BLM-induced lung fibrosis models of lung injury
Besides Idiopathic Pulmonary Fibrosis (IPF), other pathological conditions can result in pulmonary fibrosis, last but not least the persistent post-COVID syndrome [81, 82]

Summary

INTRODUCTION

The pentraxin family is an ancient group of evolutionarily conserved proteins belonging to humoral innate immunity that act as pattern recognition molecules (PRM). PTX3 gene down-regulation in lung samples may be related to active IPF pathology This recapitulates the mouse phenotype observed in vivo, with aberrant collagen deposition in Ptx3-/- mice [Figure 1 [29]], supporting the possibility that endogenous PTX3 exerts a protective role and may be involved in IPF disease. This production seems to be functionally antagonized by the production of IFN-b in these macrophages [69], that directs their anti-fibrotic phenotype [70, 71] Along these lines, apoptotic cell instillation after BLM attenuates lung injury [72] and induces PPARg, promoting lung fibrosis resolution via regulation of efferocytosis and IL-10 production [73]. PTX3 interacts with collagens and our own preliminary results indicate a possible involvement of collagen remodeling by mesenchymal cells, suggesting an effect in removing the excess of ECM from tissue parenchyma (Figure 2D) and in promoting tissue healing

CONCLUDING AND REMARKS

Findings

ETHICS STATEMENT