LAIR-1 Limits Neutrophilic Airway Inflammation

Abstract

Neutrophils are crucial to antimicrobial defense, but excessive neutrophilic inflammation induces immune pathology. The mechanisms by which neutrophils are regulated to prevent injury and preserve tissue homeostasis are not completely understood. We recently identified the collagen receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1 as a functional inhibitory receptor on airway-infiltrated neutrophils in viral bronchiolitis patients. In the current study, we sought to examine the role of LAIR-1 in regulating airway neutrophil responses in vivo . LAIR-1-deficient ( Lair1 −/− ) and wild-type mice were infected with respiratory syncytial virus (RSV) or exposed to cigarette smoke as commonly accepted models of neutrophil-driven lung inflammation. Mice were monitored for cellular airway influx, weight loss, cytokine production, and viral loads. After RSV infection, Lair1 −/− mice show enhanced airway inflammation accompanied by increased neutrophil and lymphocyte recruitment to the airways, without effects on viral loads or cytokine production. LAIR-1-Fc administration in wild type mice, which blocks ligand induced LAIR-1 activation, augmented airway inflammation recapitulating the observations in Lair1 −/− mice. Likewise, in the smoke-exposure model, LAIR-1 deficiency enhanced neutrophil recruitment to the airways and worsened disease severity. Intranasal CXCL1–mediated neutrophil recruitment to the airways was enhanced in mice lacking LAIR-1, supporting an intrinsic function of LAIR-1 on neutrophils. In conclusion, the immune inhibitory receptor LAIR-1 suppresses neutrophil tissue migration and acts as a negative regulator of neutrophil-driven airway inflammation during lung diseases. Following our recent observations in humans, this study provides crucial in-vivo evidence that LAIR-1 is a promising target for pharmacological intervention in such pathologies.

The Contribution of Neutrophils to the Pathogenesis of RSV Bronchiolitis

“…Agonistic ligation of LAIR-1 was shown to limit NET formation by BALF neutrophils in vitro. Of note, RSV-infected LAIR-1-deficient mice present with greater neutrophilic inflammation upon inoculation with RSV [118], supporting the notion that agonism of LAIR-1 is a logical strategy to ameliorate the severity of viral bronchiolitis. In a separate study performed in infants with an RSV infection, the neutrophils in the nasopharyngeal aspirates were shown to exhibit lower CD62L and CD31 (PECAM-1) and higher CD54 (ICAM-I), CD11b, and CD18 expression compared to those in peripheral blood [116].…”

Cancer immunotherapy based on blocking immune suppression mediated by an immune modulator LAIR-1

“…10 LAIR-1 can also suppress neutrophil tissue migration and acts as a negative regulator of neutrophil-driven airway inflammation during lung diseases. 34 Furthermore, C1q is a functional ligand for LAIR-1 besides collagen, and C1q-LAIR-1 interactions inhibit DC (dendritic cell) differentiation and activation, which can be reversed by LAIR-2. 20 These studies suggest that, besides suppressing T cell immune responses in the TME, interactions between LAIR-1 and collagen or C1q may result in the suppression of various immune cells.…”

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

“…This receptor is not expressed on circulating neutrophils, but may be upregulated upon migration into tissues and subsequent activation [26]. RSV-infected mice lacking functional LAIR-1 exhibited greater neutrophil influx into the airways but had no indication of enhanced viral clearance [27].…”