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Similar to immune cells, non‐hematopoietic cells recognize microbial and endogenous threats. Their response to these stimuli is dependent on the environmental context. For example, intact intestinal epithelium expresses pattern recognition receptors (PRRs) but should tolerate commensal bacteria, while damaged epithelium should respond promptly to initiate an immune response. This indicates that non‐hematopoietic cells possess mechanisms to sense environmental context and regulate their responses. Inhibitory receptors provide context sensing to immune cells. For instance, they raise the threshold for activation to prevent overzealous immune activation to harmless stimuli. Inhibitory receptors are typically studied on hematopoietic cells, but several of these receptors are expressed on non‐hematopoietic cells. Here, we review evidence for the regulation of non‐hematopoietic cells by inhibitory receptors, focusing on epithelial and endothelial cells. We explain that inhibitory receptors on these cells can sense a wide range of signals, including cell‐cell adhesion, cell‐matrix adhesion, and apoptotic cells. More importantly, they regulate various functions on these cells, including immune activation, proliferation, and migration. In conclusion, we propose that inhibitory receptors provide context to non‐hematopoietic cells by fine tuning their response to endogenous or microbial stimuli. These findings prompt to investigate the functions of inhibitory receptors on non‐hematopoietic cells more systematically. [ABSTRACT FROM AUTHOR]

Introduction: Neutrophils are crucial to antimicrobial defense, but excessive neutrophilic inflammation elicits immune pathology. Currently, no effective treatment exists to curb neutrophil activation. However, neutrophils express a variety of inhibitory receptors which may represent potential therapeutic targets to limit neutrophilic inflammation. Indeed, we previously showed that the inhibitory collagen receptor leukocyte‐associated immunoglobulin‐like receptor 1 (LAIR‐1) regulates neutrophilic airway inflammation and inhibits neutrophil extracellular trap formation. The inhibitory receptor Allergin‐1 is expressed by myeloid cells and B cells. Allergin‐1 suppresses mast cell and basophil activation, but a potential regulatory role on neutrophils remains unexplored. We aimed to demonstrate the regulation of neutrophils by Allergin‐1. Methods: We examine Allergin‐1 isoform expression on human neutrophils during homeostatic (healthy donors) and chronic inflammatory (systemic lupus erythematosus patients) conditions in comparison to other circulating leukocytes by flow cytometry. To reveal a potential role for Allergin‐1 in regulating neutrophilic inflammation, we experimentally infect wild‐type (WT) and Allergin‐1‐deficient mice with a respiratory syncytial virus (RSV) and monitor disease severity and examine cellular airway infiltrate. Flow cytometry was used to confirm Allergin‐1 expression by airway‐infiltrated neutrophils in RSV infection‐induced bronchiolitis patients. Results: Only the short 1 (S1) isoform, but not the long (L) or S2 isoform could be detected on blood leukocytes, with the exception of nonclassical monocytes, which exclusively express the S2 isoform. Allergin‐1 expression levels did not vary significantly between healthy individuals and patients with the systemic inflammatory disease on any interrogated cell type. Airway‐infiltrated neutrophils of pediatric RSV bronchiolitis patients were found to express Allergin‐1S1. However, Allergin‐1‐deficient mice experimentally infected with RSV did not show exacerbated disease or increased neutrophil airway infiltration compared to WT littermates. Conclusion: Allergin‐1 isoform expression is unaffected by chronic inflammatory conditions. In stark contrast to fellow inhibitory receptor LAIR‐1, Allergin‐1 does not regulate neutrophilic inflammation in a mouse model of RSV bronchiolitis. [ABSTRACT FROM AUTHOR]

Signal inhibitory receptor on leukocytes‐1 (SIRL‐1) is an inhibitory receptor with a hitherto unknown ligand, and is expressed on human monocytes and neutrophils. SIRL‐1 inhibits myeloid effector functions such as reactive oxygen species (ROS) production. In this study, we identify S100 proteins as SIRL‐1 ligands. S100 proteins are composed of two calcium‐binding domains. Various S100 proteins are damage‐associated molecular patterns (DAMPs) released from damaged cells, after which they initiate inflammation by ligating activating receptors on immune cells. We now show that the inhibitory SIRL‐1 recognizes individual calcium‐binding domains of all tested S100 proteins. Blocking SIRL‐1 on human neutrophils enhanced S100 protein S100A6‐induced ROS production, showing that S100A6 suppresses neutrophil ROS production via SIRL‐1. Taken together, SIRL‐1 is an inhibitory receptor recognizing the S100 protein family of DAMPs. This may help limit tissue damage induced by activated neutrophils. [ABSTRACT FROM AUTHOR]

ROS production is an important effector mechanism mediating intracellular killing of microbes by phagocytes. Inappropriate or untimely ROS production can lead to tissue damage, thus tight regulation is essential. We recently characterized signal inhibitory receptor on leukocytes-1 ( SIRL-1) as an inhibitory receptor expressed by human phagocytes. Here, we demonstrate that ligation of SIRL-1 dampens Fc receptor-induced ROS production in primary human phagocytes. In accordance, SIRL-1 engagement on these cells impairs the microbicidal activity of neutrophils, without affecting phagocytosis. The inhibition of ROS production may result from reduced ERK activation, since co-ligation of Fc receptors and SIRL-1 on phagocytes inhibited phosphorylation of ERK. Importantly, we demonstrate that microbial and inflammatory stimuli cause rapid downregulation of SIRL-1 expression on the surface of primary neutrophils and monocytes. In accordance, SIRL-1 expression levels on neutrophils in bronchoalveolar lavage fluid from patients with neutrophilic airway inflammation are greatly reduced. We propose that SIRL-1 on phagocytes sets an activation threshold to prevent inappropriate production of oxygen radicals. Upon infection, SIRL-1 expression is downregulated, allowing microbial killing and clearance of the pathogen. [ABSTRACT FROM AUTHOR]

Plasma is a rich mixture of immune regulatory factors that shape immune cell function. This immunomodulatory role of plasma is especially important in neonates. To maintain in utero feto-maternal tolerance and to allow for microbial colonization after birth, the neonatal immune system is biased against pro-inflammatory responses while favoring immune suppression. Therefore, the neonatal period provides a unique opportunity to study the physiologic mechanisms regulating the immune system. Several recent studies in neonates have identified plasma factors that play a key role in immune regulation. Insight into immune regulation by neonatal and adult plasma may have clinical implications, because plasma is easily accessible, affordable, and widely available. Herein, we review plasma-mediated immune regulation, with specific focus on neonatal plasma. We discuss how immune suppression is a key function of plasma and provide a systematic overview of the published literature regarding plasma-derived immune suppressive proteins, lipids, purines, and sugars. Finally, we outline how immune regulation by these factors, which are particularly abundant in neonatal plasma, may eventually be used to treat immune-mediated diseases, such as autoimmune, allergic, and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Objective Human leukocyte-associated immunoglobulin-like receptor 1 (hLAIR-1) is an immune inhibitory receptor for collagen that is expressed on most immune cells. We previously showed that the LAIR-1-collagen interaction could be antagonized by the secreted homolog hLAIR-2, which can be detected in the synovial fluid of rheumatoid arthritis (RA) patients. In addition, the extracellular part of hLAIR-1 is a putative antagonist upon shedding from the cell membrane. The purpose of this study was to determine the relative roles of hLAIR-2 and soluble hLAIR-1 (shLAIR-1) in the regulation of the LAIR-1-collagen interaction. Methods The ability of recombinant LAIR proteins to abrogate LAIR-1-collagen binding was tested by flow cytometry and adhesion assays. Collagen binding capacity was analyzed by surface plasmon resonance. Plasma, urine, and synovial fluid were screened for the presence of sLAIR-1 and LAIR-2 by enzyme-linked immunosorbent assay. Results Recombinant LAIR-2 proteins abrogated the binding of collagen to LAIR-1 more efficiently than did recombinant sLAIR-1. Consistent with these findings, surface plasmon resonance analysis showed that LAIR-2 had a higher affinity for collagen than did LAIR-1. Activated CD4+ T cells were the main producers of LAIR-2, whereas the source of sLAIR-1 remains elusive. Both soluble LAIR-1 and LAIR-2 could be detected in the plasma and urine of healthy control subjects and patients with RA. Urinary levels of both proteins were significantly increased in RA patients, and LAIR-2 levels in urine were significantly correlated with markers of inflammation. Conclusion Our data suggest that LAIR-2 is a more potent antagonist of LAIR-1 function in vivo, while both sLAIR-1 and LAIR-2 are potential biomarkers that may be used to monitor urine samples for evidence of systemic inflammation. [ABSTRACT FROM AUTHOR]

CD200R is an inhibitory receptor involved in the regulation of myeloid cells. It recruits Dok-1 and Dok-2, which are potent inhibitors of the Ras signalling pathway used by colony-stimulating factor (CSF) receptors. Dok-1/Dok-2 double knockout (DKO) mice develop leukaemia at 10–12 months of age. We investigated whether disturbed CD200R signalling could be responsible for this phenotype. Therefore, we studied whether CD200−/− mice have altered myelopoiesis and develop leukaemia. We report that CD200R is expressed on haematopoietic progenitor cells. However, CD200−/− mice have normal numbers of myeloid progenitors in the bone marrow and these cells have normal proliferative capacity. These results indicate that the development of leukaemia in Dok-1/Dok-2 DKO mice is not solely due to an absence of CD200R signalling. In addition, we show that the previously reported enhanced numbers of myeloid cells do not occur in all CD200−/− mice. We determined whether variations in the numbers of peripheral myeloid cells were due to an enhanced response to granulocyte-CSF (G-CSF) or an inflammatory stimulus. Mobilisation of immature neutrophils via G-CSF and infiltration of mature neutrophils and macrophages upon thioglycolate injection were not altered in CD200−/− mice. We conclude that CD200−/− mice exhibit normal myelopoiesis and that development of leukaemia in Dok-1/Dok-2 DKO mice is not caused by a lack of CD200-mediated CD200R signalling. [ABSTRACT FROM AUTHOR]

The leukocyte-associated Ig-like receptor-1 (LAIR-1) is capable of inhibiting immune cell function through interaction with collagens. LAIR is expressed on the majority of peripheral blood mononuclear cells. The abundant expression of both receptor and ligand calls for regulatory mechanisms to relieve the continuous interaction between collagens and LAIR-1. This regulation may occur at the expression level of the receptor. Here, we report that LAIR-1 is indeed differentially expressed during human T cell differentiation. Naive CD4 and CD8 T cells as well as CD8 T cells of the effector phenotype express higher levels of LAIR-1 compared to memory T cells. In vitro stimulation revealed a decrease in LAIR-1 expression upon activation, and the lower LAIR-1 expression on CD127 T cells suggests that activation-induced down-modulation of LAIR-1 may also occur in vivo. Furthermore, crosslinking of LAIR-1 on primary T cells results in an inhibition of T cell function. Our data suggest that regulated expression of LAIR-1 and the subsequent change in the threshold for activation may be a mechanism to modulate inhibition of the immune system. [ABSTRACT FROM AUTHOR]

Most inhibitory receptors in the immune system contain one or several immunoreceptor tyrosine-based inhibitory motifs (ITIM) and recruit the SH2 domain-containing phosphatases SHP-1, SHP-2 and/or SHIP, which are generally believed to be essential for the inhibitory function. However, it has not been systematically investigated whether ITIM-bearing receptors exert their function through alternative interactions. Here we describe that leukocyte-associated Ig-like receptor (LAIR)-1 has inhibitory function in DT40 chicken B cells that lack both SHP-1 and SHP-2. In addition, we found that LAIR-1 did not recruit SHIP upon phosphorylation. Thus, LAIR-1 can function independently from SH2 domain-containing phosphatases and must recruit at least one other signaling molecule. Using a yeast-tri-hybrid system, we found that phosphorylated LAIR-1 bound the C-terminal Src kinase (Csk). The interaction required the SH2 domain of Csk and phosphorylation of the tyrosine in the N-terminal ITIM of LAIR-1. We propose that Csk is an additional player in the regulation of the immune system by ITIM-bearing receptors. [ABSTRACT FROM AUTHOR]