FPRs: linking innate immune system and fibrosis

Fibrosis is a deregulated and uncontrolled repair process that recapitulates features of embryonic development and normal wound healing. The inappropriate repair by connective tissue, characterized by an excessive deposition of collagen and other extracellular matrix components, is now known as an important feature of many chronic diseases, including myocardial infarction, glomerulosclerosis, idiopathic pulmonary fibrosis, liver cirrhosis and systemic sclerosis (SSc). In SSc, the tightly regulated and self-limited response to injury, normally leading to tissue regeneration, is subverted into fibrosis, with disruption of tissue architecture and loss of functional integrity; both the skin and the internal organs can be affected. An inappropriate fibroblast activation and the subsequent accumulation of myofibroblasts in affected tissues underlie this switch. A subgroup of resident fibroblasts, in response to specific stimuli (e.g. transforming growth factor-β), transdifferentiate into myofibroblasts expressing high levels of α-smooth muscle actin (α-SMA) and playing a significant functional role in pathologic fibrosis [1]. N-formyl peptide (fMLF) receptors (FPRs) are a family of pattern recognition receptors, regulating innate responses. FPRs, by interacting with several structurally diverse proand anti-inflammatory ligands, possess important regulatory effects in multiple pathological conditions, including inflammation and cancer. In addition, all FPRs expressed on epithelia seem to be required for wound repair and restitution of barrier integrity, by facilitating epithelial cell migration, proliferation, and neo-angiogenesis [2]. Three variants of FPRs have been identified in humans: FPR1, FPR2, and FPR3. FPR1 is activated by nanomolar concentrations of fMLF. FPR2 is a promiscuous receptor activated in response to high concentrations of fMLF, and to viral, bacterial, endogenous and synthetic peptides. Hp(2-20), uPAR84-95, and F2L are natural ligands of FPR3. The synthetic peptide WKYMVm is an FPR panagonist, depending on its concentration [3]. Several functions of FPRs occur through the interaction with the urokinase-type plasminogen activator (uPA) receptor (uPAR). uPAR is formed by three Editorial