Leukocyte Associated Immunoglobulin Like Receptor 1 Regulation and Function on Monocytes and Dendritic Cells During Inflammation

Abstract

Inhibitory receptors are crucial immune regulators and are essential to prevent exacerbated responses, thus contributing to immune homeostasis. Leukocyte associated immunoglobulin like receptor 1 (LAIR-1) is an immune inhibitory receptor which has collagen and collagen domain containing proteins as ligands. LAIR-1 is broadly expressed on immune cells and has a large availability of ligands in both circulation and tissues, implicating a need for tight regulation of this interaction. In the current study, we sought to examine the regulation and function of LAIR-1 on monocyte, dendritic cell (DC) and macrophage subtypes, using different in vitro models. We found that LAIR-1 is highly expressed on intermediate monocytes as well as on plasmacytoid DCs. LAIR-1 is also expressed on skin immune cells, mainly on tissue CD14 + cells, macrophages and CD1c + DCs. In vitro, monocyte and type-2 conventional DC stimulation leads to LAIR-1 upregulation, which may reflect the importance of LAIR-1 as negative regulator under inflammatory conditions. Indeed, we demonstrate that LAIR-1 ligation on monocytes inhibits toll like receptor (TLR)4 and Interferon (IFN)-α-induced signals. Furthermore, LAIR-1 is downregulated on GM-CSF and IFN-γ monocyte-derived macrophages and monocyte-derived DCs. In addition, LAIR-1 triggering during monocyte derived-DC differentiation results in significant phenotypic changes, as well as a different response to TLR4 and IFN-α stimulation. This indicates a role for LAIR-1 in skewing DC function, which impacts the cytokine expression profile of these cells. In conclusion, we demonstrate that LAIR-1 is consistently upregulated on monocytes and DC during the inflammatory phase of the immune response and tends to restore its expression during the resolution phase. Under inflammatory conditions, LAIR-1 has an inhibitory function, pointing toward to a potential intervention opportunity targeting LAIR-1 in inflammatory conditions.

Immune Modulatory Properties of Collagen in Cancer

“…LAIR-1 is expressed by the majority of myeloid cells, including monocytes and macrophages, and it has been reported to have inhibitory effects on their cellular functions ( 93 ). In monocytes, LAIR-1 ligation with an agonistic antibody inhibited TLR-mediated activation ( 145 ). Additionally, cultivation of M1-stimulated murine or human macrophages on surfaces coated with LAIR-1 ligand peptide has been shown to result in decreased secretion of the pro-inflammatory cytokine TNFα as well as T cell attracting chemokines ( 146 ).…”

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“…In our analysis, the mRNA expression of LAIR2 in Tregs and partial CD8+/GZMB+ T cells, in comparison to LAIR1, which was widely expressed by various cell populations, could be an indicator of exhaustive immune status. Former studies showed LAIR1 was expressed by macrophages, dendritic cells, as well as other CD14+ cells in inflammation, and scientists hypothesized LAIR1 could be both a threshold receptor and negative feedback receptor ( 64 , 65 ). In our analysis, LAIR1 was not related to immune infiltration status in CHOL, and we believed mRNA expression of LAIR2 may be increased to offset LAIR1’s function in feedback loop, highlighting the role of baseline LAIR2 expression.…”

The Genomic Organization of the LILR Region Remained Largely Conserved Throughout Primate Evolution: Implications for Health And Disease

“…The expression of LAIR is broadly confined to peripheral blood lymphocytes, including NK cells, T and B lymphocytes, neutrophils, monocytes, and macrophages (21)(22)(23)(24)(25). LAIR1 and LAIR2 gene products are both collagen-binding receptors, and play a key role in controlling tissue inflammation (24,(26)(27)(28)(29).…”