The role of LAIR-1 in regulating macrophage pro-fibrotic activity in idiopathic pulmonary fibrosis - 09/05/26

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease of unknown etiology, characterized by the irreversible accumulation of extracellular matrix components, notably collagen, in the pulmonary interstitium and alveolar spaces. Studies in the field highlight a central role for lung macrophages in driving fibrosis through the secretion of pro-fibrotic mediators. Given their plasticity, reprogramming macrophages away from fibrotic activity is a promising therapeutic strategy. Immune checkpoints play a critical role in maintaining immune homeostasis and regulating inflammation. Among them, leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory immune checkpoint and a collagen receptor, is mainly expressed on macrophages and suggested as a regulator of lung immunity. The deleterious role of LAIR-1 is confirmed in cancer, mainly through promoting the collagenic matrix in tumors; however, studies are still needed to understand its role in fibrotic diseases. Thus, our study explores LAIR-1 role in regulating macrophage fibrotic activity in IPF.

In silico and flow cytometry analyses were used to assess LAIR-1 expression in cells from IPF patients and controls. Correlation between LAIR-1 levels and various clinical parameters was evaluated. A human monoclonal antibody targeting LAIR-1 was developed to study the implication of LAIR-1 inhibition and was tested ex vivo human alveolar macrophage (AM) cultures. RNA sequencing and pathways analysis were carried out to determine the effect of LAIR-1 blockade on macrophage phenotype and fibrotic gene expression. Supernatants from anti-LAIR-1-treated AM were recovered to assess their effect on primary fibroblasts from IPF patients.

Reanalysis of scRNA-seq IPF atlas datasets found that LAIR-1 is predominantly expressed on macrophages in the lung. Flow cytometry results from our human cohort confirmed dysregulated expression of LAIR-1 in IPF patients’ AM, and interestingly, correlated with total lung capacity. LAIR-1 antagonist treatment resulted in enhanced expression of pro-fibrotic genes, including SPP1, LIF and MMPs, with enrichment of a set of genes in a pathway responsible for fibroblast activity. Additionally, LAIR-1 antagonist enhanced the secretion of pro-fibrotic mediators such as IL1RA, IL-6, CCL17, and CCL22. Further, incubation of IPF fibroblasts with treated AM supernatants promoted their activation, as evidenced by increased COL1A1 expression.

Our data suggest that LAIR-1 functions as a modulator of macrophage fibrotic activity in IPF. Antagonist treatment promotes pro-fibrotic reprogramming in AM, leading to the secretion of soluble mediators that could enhance the activation of fibroblasts. Overall, this study uncovers a new potential immune target in IPF.