Paired Immunoglobulin-like Receptor B Research Articles

Effects of porcine epidemic diarrhea virus infection on CD21+ B cells activation

Porcine epidemic diarrhea virus (PEDV) is a devastating pathogen of acute- gastrointestinal infectious diseases, which can cause vomiting, diarrhea, dehydration and high morbidity and mortality among neonatal piglets. Humoral immunity plays a vital role in the host anti-PEDV infection process, but the mechanism of PEDV-induced B-cell immune response remains unknown. In this study, the effects of PEDV infection on CD21+ B cell activation were systematically analyzed through animal experiments. Enzyme-linked immunosorbent assays (ELISA) revealed that low levels of serum-specific IgA, IgM, or IgG were detected in piglets after PEDV infection, respectively. Serum interleukin (IL)-6 levels increased significantly at 4 d after infection, and the levels of IL-4, B-cell activating factor (BAFF), interferon (IFN)-γ, transforming growth factor (TGF)-β and IL-10 decreased at 7 d after infection. Fluorescence-activated cell sorting (FACS) showed that expression levels of CD21, MHC Ⅱ, CD40, and CD38 on B cell surfaces were significantly higher. In contrast, the proportions of CD21+IgM+ B cells were decreased in peripheral blood mononuclear cells (PBMCs) from the infected piglets. No differences were found in the percentage of CD21+CD80+ and CD21+CD27+ B cells in PBMCs from the infected piglets. In addition, the number of CD21+B cells in PBMCs stimulated with PEDV in vitro was significantly lower. No significant change in the mRNA expression of BCR molecules was found while the expression levels of paired immunoglobulin-like receptor B (PIR-B), B cell adaptor molecule of 32 kDa (Bam32) and BAFF were decreased. In conclusion, our research demonstrates that virulent strains of PEDV profoundly impact B cell activation, leading to alterations in phenotypic expression and BCR signaling molecules. Furthermore, this dysregulation results in compromised specific antibody secretion and perturbed cytokine production, highlighting the intricate immunological dysfunctions induced by PEDV infection.

The leukocyte immunoglobulin-like receptor gp49B1, coexpressed with c-Kit, modulates hematopoiesis and B cell leukemia development

A better understanding of cell-intrinsic factors involved in regulating stem cells and cancer cells will help advance stem cell applications and cancer cell treatment. Previously, we showed that leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse ortholog, paired immunoglobulin-like receptor B (PIRB), promote blood stem cell and leukemia development. Another unique mouse paralog to PIRB called gp49B1 was also discovered. However, the roles of gp49B1 in hematopoietic stem cells and leukemia development are largely unknown. Here, we found that gp49B1 is expressed on LSK cells of mouse neonatal hematopoietic organs and is positively correlated with c-Kit expression. However, in noncompetitive and competitive repopulation assays, neonatal splenic gp49B1-positive and c-Kit-highly expressed LSK cells exhibited poor engraftment potential and lymphoid lineage bias. Moreover, in a mouse N-Myc-induced precursor B-acute lymphoblastic leukemia (pre-B ALL) model, we found that gp49B1 deficiency or low levels of c-Kit led to a delay in leukemia development. Together, our results suggest that gp49B1 expressed on hematopoietic progenitor cells supports hematopoietic and leukemia development.

PIR-B Regulates CD4+ IL17a+ T-Cell Survival and Restricts T-Cell-Dependent Intestinal Inflammatory Responses.

Background & AimsCD4+ T cells are regulated by activating and inhibitory cues, and dysregulation of these proper regulatory inputs predisposes these cells to aberrant inflammation and exacerbation of disease. We investigated the role of the inhibitory receptor paired immunoglobulin-like receptor B (PIR-B) in the regulation of the CD4+ T-cell inflammatory response and exacerbation of the colitic phenotype.MethodsWe used Il10-/- spontaneous and CD4+CD45RBhi T-cell transfer models of colitis with PIR-B-deficient (Pirb-/-) mice. Flow cytometry, Western blot, and RNA sequencing analysis was performed on wild-type and Pirb-/- CD4+ T cells. In silico analyses were performed on RNA sequencing data set of ileal biopsy samples from pediatric CD and non–inflammatory bowel disease patients and sorted human memory CD4+ T cells.ResultsWe identified PIR-B expression on memory CD4+ interleukin (IL)17a+ cells. We show that PIR-B regulates CD4+ T-helper 17 cell (Th17)-dependent chronic intestinal inflammatory responses and the development of colitis. Mechanistically, we show that the PIR-B– Src-homology region 2 domain-containing phosphatase-1/2 axis tempers mammalian target of rapamycin complex 1 signaling and mammalian target of rapamycin complex 1–dependent caspase-3/7 apoptosis, resulting in CD4+ IL17a+ cell survival. In silico analyses showed enrichment of transcriptional signatures for Th17 cells (RORC, RORA, and IL17A) and tissue resident memory (HOBIT, IL7R, and BLIMP1) networks in PIR-B+ murine CD4+ T cells and human CD4+ T cells that express the human homologue leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3). High levels of LILRB3 expression were associated strongly with mucosal injury and a proinflammatory Th17 signature, and this signature was restricted to a treatment-naïve, severe pediatric CD population.ConclusionsOur findings show an intrinsic role for PIR-B/LILRB3 in the regulation of CD4+ IL17a+ T-cell pathogenic memory responses.

LILRB receptor-mediated regulation of myeloid cell maturation and function.

The leukocyte immunoglobulin-like receptor (LILR) family comprises a set of paired immunomodulatory receptors expressed among human myeloid and lymphocyte cell populations. While six members of LILR subfamily A (LILRA) associate with membrane adaptors to signal via immunoreceptor tyrosine-based activating motifs(ITAM), LILR subfamily B (LILRB) members signal via multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM). Ligand specificity of some LILR family members has been studied in detail, but new perspective into the immunoregulatory aspects of this receptor family in human myeloid cells has been limited. LILRB receptors and the murine ortholog, paired immunoglobulin-like receptor B (PIRB), have been shown to negatively regulate maturation pathways in myeloid cells including mast cells, neutrophils, dendritic cells, as well as B cells. Our laboratory further demonstrated in mouse models that PIRB regulated functional development of myeloid-derived suppressor cell and the formation of a tumor-permissive microenvironment. Based on observations from the literature and our own studies, our laboratory is focusing on how LILRs modulate immune homeostasis of human myeloid cells and how these pathways may be targeted in disease states. Integrity of this pathway in tumor microenvironments, for example, permits a myeloid phenotype that suppresses antitumor adaptive immunity. This review presents the evidence supporting a role of LILRs as myeloid cell regulators and ongoing efforts to understand the functional immunology surrounding this family.

Soluble LILRA3 promotes neurite outgrowth and synapses formation through a high-affinity interaction with Nogo 66.

Inhibitory proteins, particularly Nogo 66, a highly conserved 66-amino-acid loop of Nogo A (an isoform of RTN4), play key roles in limiting the intrinsic capacity of the central nervous system (CNS) to regenerate after injury. Ligation of surface Nogo receptors (NgRs) and/or leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue the paired immunoglobulin-like receptor B (PIRB) by Nogo 66 transduces inhibitory signals that potently inhibit neurite outgrowth. Here, we show that soluble leukocyte immunoglobulin-like receptor A3 (LILRA3) is a high-affinity receptor for Nogo 66, suggesting that LILRA3 might be a competitive antagonist to these cell surface inhibitory receptors. Consistent with this, LILRA3 significantly reversed Nogo-66-mediated inhibition of neurite outgrowth and promoted synapse formation in primary cortical neurons through regulation of the ERK/MEK pathway. LILRA3 represents a new antagonist to Nogo-66-mediated inhibition of neurite outgrowth in the CNS, a function distinct from its immune-regulatory role in leukocytes. This report is also the first to demonstrate that a member of LILR family normally not expressed in rodents exerts functions on mouse neurons through the highly homologous Nogo 66 ligand.

ANGPTL2/LILRB2 signaling promotes the propagation of lung cancer cells.

Immune inhibitory receptors expressed on various types of immune cells deliver inhibitory signals that maintain the homeostasis of the immune system. Recently we demonstrated that leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) and its murine homolog, paired immunoglobulin-like receptor B (PIRB), are expressed on hematopoietic stem cells and acute myeloid leukemia stem cells and function in maintenance of stemness. Herein, we determined that both LILRB2 and its soluble ligand ANGPTL2 are highly expressed in non-small cell lung cancer (NSCLC) samples, and levels are adversely related to patient prognosis. Inhibition of LILRB2 expression in NSCLC cell lines, such as A549 cells, resulted in a dramatic decrease in proliferation, colony formation, and migration. Mechanistic analyses indicated that ANGPTL2 binds LILRB2 to support the growth of lung cancer cells and that the SHP2/CaMK1/CREB axis controls the proliferation of lung cancer cell lines. Our results suggest that signaling involving ANGPTL2 and LILRB2 is important for lung cancer development and represents a novel target for treatment of this type of cancer.

Potential Roles of HLA-G and MDSCs in Virus Infection

As a subset of myeloid progenitors and immature myeloid cells, previous studies revealed that MDSCs could be generated in the presence of various cytokines and growth factors, including G-CSF, GM-CSF, PGE2, VEGF, IL-6, IL-1β and TNF-α [4]. To be noted, through binding to the murine receptor paired immunoglobulin like receptor-B (PIR-B) expressed on MDSCs, human leukocyte antigen-G (HLA-G) has been found with the capability to contribute the expansion and suppressive functions of MDSCs [5].

Spatio-temporal expression of paired immunoglobulin-like receptor-B in the adult mouse brain after focal cerebral ischaemia

Primary objective: Paired immunoglobulin-like receptor-B (PirB) is another receptor, except for the Nogo receptor, that is involved in inhibition of axons regeneration after central nervous system injury. However, the expression of PirB in focal cerebral ischaemic brain remains unclear. Herein, this study investigated spatial-temporal expression of PirB in the mouse brain following transient focal cerebral ischaemia.Methods and procedure: Adult male C57BL/6 mice underwent a 60-minute transient occlusion of middle cerebral artery. Mice were killed and brain samples were harvested at 30 minutes, 2 hours, 24 hours, 3 days and 7 days after reperfusion. Expression of PirB in the brain was determined by reverse transcriptase-polymerase chain reaction (RT-PCR), western blot analysis and immunohistochemical staining.Main outcomes and results: The results showed that PirB was mainly expressed in ischaemic penumbra. PirB mRNA and protein expression began to increase at 2 hours, peaked at 24 hours and lasted for 7 days after reperfusion in the ischaemic penumbra. By using immunofluorescence, PirB signals were co-localized with NeuN-positive neurons.Conclusion: PirB expression is up-regulated in ischaemic penumbra following transient focal cerebral ischaemia. PirB expression in neurons may play important pathological roles in the inhibition of axonal regeneration after stroke, suggesting that the inhibition of PirB expression may enhance axonal regeneration and functional recovery after stroke.

Paired Immunoglobulin-Like Receptor–B Inhibits Pulmonary Fibrosis by Suppressing Profibrogenic Properties of Alveolar Macrophages

Macrophages are lung-resident cells that play key roles in fibrosis. Surprisingly, pathways that inhibit macrophage functions, especially in idiopathic pulmonary fibrosis (IPF), receive little attention. The cell-surface molecule paired immunoglobulin-like receptor B (PIR-B) can suppress macrophage activation. However, its role in pulmonary fibrosis remains unknown. We sought to define the role of PIR-B in IPF. The expression of PIR-B was assessed (by quantitative PCR and flow cytometry) after bleomycin treatment. Differential cell counts, histopathology, and profibrogenic-mediator expression, for example, collagen, α-smooth muscle actin, resistin-like molecule-α (Relm-α), matrix metalloproteinase (MMP)-12, and tissue inhibitor of metalloproteinase (TIMP)-1, were determined (by ELISA quantitative PCR and flow cytometry) in the lungs of wild-type and Pirb(-/-) mice after bleomycin or IL-4 treatment. Bone marrow-derived wild-type and Pirb(-/-) macrophages were stimulated with IL-4 and assessed for Relm-α and MMP-12 expression. PIR-B was up-regulated in lung myeloid cells after bleomycin administration. Bleomycin-treated Pirb(-/-) mice displayed increased lung histopathology and an increased expression of collagen and of the IL-4-associated profibrogenic markers Relm-α, MMP-12, TIMP-1, and osteopontin, which were localized to alveolar macrophages. Increased profibrogenic mediator expression in Pirb(-/-) mice was not attributable to increased IL-4/IL-13 concentrations, suggesting that PIR-B negatively regulates IL-4-induced macrophage activation. Indeed, IL-4-treated Pirb(-/-) mice displayed increased Relm-α expression and Relm-α(+) macrophage concentrations. IL-4-activated Pirb(-/-) macrophages displayed increased Relm-α and MMP-12 induction. Finally, leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3)/immunoglobulin-like transcript-5, the human PIR-B orthologue, was expressed and up-regulated in lung biopsies from patients with IPF. Our results establish a key role for PIR-B in IPF, likely via the regulation of macrophage activation. Therefore, PIR-B/LILRB3 may offer a possible target for suppressing macrophage profibrogenic activity in IPF.

Stem cell factor-dependent mast cell proliferation, maturation and activity can be regulated by inhibitory receptors

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Brzezińska-Błaszczyk E, Bąbolewska E. Review paperStem cell factor-dependent mast cell proliferation, maturation and activity can be regulated by inhibitory receptors. Central European Journal of Immunology. 2013;38(1):134-140. doi:10.5114/ceji.2013.34371. APA Brzezińska-Błaszczyk, E., & Bąbolewska, E. (2013). Review paperStem cell factor-dependent mast cell proliferation, maturation and activity can be regulated by inhibitory receptors. Central European Journal of Immunology, 38(1), 134-140. https://doi.org/10.5114/ceji.2013.34371 Chicago Brzezińska-Błaszczyk, Ewa, and Edyta Bąbolewska. 2013. "Review paperStem cell factor-dependent mast cell proliferation, maturation and activity can be regulated by inhibitory receptors". Central European Journal of Immunology 38 (1): 134-140. doi:10.5114/ceji.2013.34371. Harvard Brzezińska-Błaszczyk, E., and Bąbolewska, E. (2013). Review paperStem cell factor-dependent mast cell proliferation, maturation and activity can be regulated by inhibitory receptors. Central European Journal of Immunology, 38(1), pp.134-140. https://doi.org/10.5114/ceji.2013.34371 MLA Brzezińska-Błaszczyk, Ewa et al. "Review paperStem cell factor-dependent mast cell proliferation, maturation and activity can be regulated by inhibitory receptors." Central European Journal of Immunology, vol. 38, no. 1, 2013, pp. 134-140. doi:10.5114/ceji.2013.34371. Vancouver Brzezińska-Błaszczyk E, Bąbolewska E. Review paperStem cell factor-dependent mast cell proliferation, maturation and activity can be regulated by inhibitory receptors. Central European Journal of Immunology. 2013;38(1):134-140. doi:10.5114/ceji.2013.34371.

Mast cell inhibitory receptors

Mast cells play an important role in diverse physiological mechanisms as well as taking part in antimicrobial defense. What is more, these cells are important regulators of a number of pathophysiological processes, involving allergic reactions. Therefore, it seems to be very important to know and understand the factors and receptors influencing mast cell activity. Nowadays it is well established that activating signals are counterbalanced by negative or inhibition signals transmitted by inhibitory receptors containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Inhibitory receptor engagement leads to ITIM tyrosine phosphorylation, the recruitment and activation of protein tyrosine phosphatases such as SHP-1, SHP-2 and/or SHIP, and the dephosphorylation of activating receptor associated proteins. There is growing evidence that a number of inhibitory receptors have been identified on mast cells. The scope of this paper is to present the current knowledge on mast cell-associated inhibitory receptors, such as FcγRIIB, paired immunoglobulin-like receptor B (PIR-B), CD300, CD172a, gp49B1, CD200R, sialic acid-binding immunoglobulin-like lectin (Siglec) molecules, CD305, allergin-1, mast cell function-associated antigen (MAFA), and CD72. The role of these inhibitory receptors in regulation mast cell activity is also discussed.

Regulation of plasmacytoid dendritic cell responses by PIR-B

AbstractPlasmacytoid dendritic cells (PDCs) produce type I interferons (IFNs) in response to viral nucleic acids to exert antiviral immunity. However, PDCs are related to the progress and severity of autoimmune diseases, such as systemic lupus erythematosus, because they respond to host DNA. Therefore, the regulation of PDC activation is critical for maintaining adequate immune responses. Here we show that an inhibitory major histocompatibility complex class I receptor, paired immunoglobulin-like receptor B (PIR-B), suppressed Fms-like tyrosine kinase 3 ligand-induced PDC differentiation in BM cells, as well as Toll-like receptor 9-mediated IFN-α production by PDCs, through the dephosphorylation of STAT1/STAT2. In particular, PIR-B inhibited IFN-α–mediated STAT phosphorylation, suggesting that PIR-B negatively regulates the positive feedback mechanism of IFN-α secretion triggered by Toll-like receptor 9. These results demonstrate a novel regulatory role for PIR-B in PDCs.

The p75 receptor mediates axon growth inhibition through an association with PIR-B

The Nogo receptor and paired immunoglobulin-like receptor B (PIR-B) are receptors for three myelin-derived axon-growth inhibitors, including myelin-associated glycoprotein (MAG). In this study, we report that the p75 receptor is required for the signal transduction of PIR-B, which interacted with p75 upon ligand binding. In addition, p75 was required for activation of Src homology 2-containing protein tyrosine phosphatase (SHP), which is induced by MAG binding to PIR-B. Mice carrying a mutation in the p75 gene showed promotion of axonal regeneration after optic nerve injury. Thus, our results indicate that p75 has a critical role in axon growth inhibition in specific neuronal tracts.

Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17

The expression of HLA-G by malignant cells has been proposed as a tumor escape mechanism from immunosurveillance. However, although the inhibitory effect of HLA-G on antitumoral immune effectors has been documented in vitro, it remains to be resolved in vivo. In this context, the development of an animal model is now a priority to establish the proof of concept that an HLA-G(+) tumor cell develops and tolerizes the host antitumor immune response in vivo. In the present study, we provide the first in vivo evidence of such a role by a xenotumor model in mice based on the interactions between human HLA-G and the murine paired immunoglobulin-like receptor-B (PIR-B). We demonstrate that human tumor cells expressing HLA-G grow in an immunocompetent host by affecting both innate and adaptive immunity. Expansion of blood myeloid-derived CD11b(+)Gr1(+)PIR-B(+) suppressor cells, loss of peripheral T cells, and cytokinic balance in favor of Th2 versus Th1/Th17 constitute the main mechanisms by which HLA-G promotes tumor expansion. These data demonstrate for the first time that HLA-G plays a crucial role in in vivo tumor evasion. Finally, blocking HLA-G function by a specific Ab inhibits the in vivo development of the tumor, offering a new innovative therapeutic strategy in cancer.

Myelin suppresses axon regeneration by PIR-B/SHP-mediated inhibition of Trk activity

Paired immunoglobulin-like receptor B (PIR-B) partially mediates the regeneration-inhibiting effects of the myelin-derived protein Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). In this study, we report that inhibition of the PIR-B signaling cascades in neurons enhances axon regeneration in the central nervous system (CNS). Binding of MAG to PIR-B led to the association of PIR-B with tropomyosin receptor kinase (Trk) neurotrophin receptors. Src homology 2-containing protein tyrosine phosphatase (SHP)-1 and SHP-2, which were recruited to PIR-B upon MAG binding, functioned as Trk tyrosine phosphatases. Further, SHP-1 and SHP-2 inhibition reduced MAG-induced dephosphorylation of Trk receptors and abolished the inhibitory effect of MAG on neurite growth. Thus, PIR-B associated with Trk to downregulate basal and neurotrophin-regulated Trk activity through SHP-1/2 in neurons. Moreover, in vivo transfection of small interfering RNA (siRNA) for SHP-1 or SHP-2 induced axonal regeneration after optic nerve injury in mice. Our results thus identify a new molecular target to enhance regeneration of the injured CNS.

Paired Immunoglobin-like Receptor-B Regulates the Suppressive Function and Fate of Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSCs) bear characteristics of precursors for both M1 and M2 macrophages. The molecular mechanism underlying the differentiation into M1 and M2 macrophages and the relationship of this differentiation to antitumor responses remains largely undefined. Herein, we investigate the potential function of paired immunoglobulin-like receptor B (PIR-B), also known as leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3) in MDSC differentiation, and its role in tumor-induced immunity. Our studies indicated that MDSCs genetically ablated for PIR-B (Lilrb3(-/-)) underwent a specific transition to M1-like cells when entering the periphery from bone marrow, resulting in decreased suppressive function, regulatory Tcell activation activity, primary tumor growth, and lung metastases. Activation of Toll-like receptor (TLR), signal transducers, and activators of transcription 1 (STAT1), and nuclear factor-kappa B (NF-κB) signaling in Lilrb3(-/-) MDSC promoted the acquisition of M1 phenotype. Inhibition of the PIR-B signaling pathway promoted MDSC differentiation into M1 macrophages.

Paired Immunoglobulin-like Receptor B Knockout Does Not Enhance Axonal Regeneration or Locomotor Recovery after Spinal Cord Injury

Myelin components that inhibit axonal regeneration are believed to contribute significantly to the lack of axonal regeneration noted in the adult central nervous system. Three proteins found in myelin, Nogo, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein, inhibit neurite outgrowth in vitro. All of these proteins interact with the same receptors, namely, the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PIR-B). As per previous reports, corticospinal tract (CST) regeneration is not enhanced in NgR-knock-out mice after spinal cord injury. Therefore, we assessed CST regeneration in PIR-B-knock-out mice. We found that hindlimb motor function, as assessed using the Basso mouse scale, footprint test, inclined plane test, and beam walking test, did not differ between the PIR-B-knock-out and wild-type mice after dorsal hemisection of the spinal cord. Further, tracing of the CST fibers after injury did not reveal enhanced axonal regeneration or sprouting in the CST of the PIR-B-knock-out mice. Systemic administration of NEP1-40, a NgR antagonist, to PIR-B knock-out mice did not enhance the regenerative response. These results indicate that PIR-B knock-out is not sufficient to induce extensive axonal regeneration after spinal cord injury.

Paired Immunoglobulin-Like Receptor B (PIR-B) Negatively Regulates Macrophage Activation in Experimental Colitis

Innate and adaptive immune responses are regulated by cross talk between activation and inhibitory signals. Dysregulation of the inhibitory signal can lead to aberrant chronic inflammatory diseases such as the inflammatory bowel diseases (IBD). Little is known about negative regulation of innate intestinal immune activation. We examined the role of the inhibitory receptor paired immunoglobulin-like receptor B (PIR-B) in the regulation of macrophage function in innate intestinal immunity. We examined the susceptibility of Pirb-/- and wild-type (WT) mice to dextran sodium sulfate (DSS)-induced colitis. We assessed proinflammatory cytokine release and mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) activation in Pirb-/- and WT macrophages following Escherichia coli stimulation. Macrophage transfer experiments were performed to define the role of PIR-B in the negative regulation of macrophage function in DSS-induced colitis. We also assessed expression of PIR-B human homologues (immunoglobulin-like transcript [ILT]-2 and ILT-3) in colon biopsy samples from healthy individuals (controls) and patients with IBD. Pirb-/- mice had increased susceptibility to DSS-induced colitis. In vitro analysis showed increased production of proinflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor alpha) and activation of MAPK and NF-kappaB in Pirb-/- macrophages following bacterial activation. Adoptive transfer of bone marrow-derived Pirb-/- macrophages into WT mice was sufficient to increase disease susceptibility. ILT-2 and ILT-3 were expressed on CD68+ and CD68- mononuclear cells and intestinal epithelium in colon biopsy samples from patients and controls. PIR-B negatively regulates macrophage functions in response to pathogenic bacteria and chronic intestinal inflammatory responses. Inhibitory receptors such as PIR-B might be used as therapeutic targets for treatment of patients with IBD.

Ly49Q, an ITIM-bearing NK receptor, positively regulates osteoclast differentiation

Osteoclasts, multinucleated cells that resorb bone, play a key role in bone remodeling. Although immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling is critical for osteoclast differentiation, the significance of immunoreceptor tyrosine-based inhibitory motif (ITIM) has not been well understood. Here we report the function of Ly49Q, an Ly49 family member possessing an ITIM motif, in osteoclastogenesis. Ly49Q is selectively induced by receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) stimulation in bone marrow-derived monocyte/macrophage precursor cells (BMMs) among the Ly49 family of NK receptors. The knockdown of Ly49Q resulted in a significant reduction in the RANKL-induced formation of tartrate-resistance acid phosphatase (TRAP)-positive multinucleated cells, accompanied by a decreased expression of osteoclast-specific genes such as Nfatc1, Tm7sf4, Oscar, Ctsk, and Acp5. Osteoclastogenesis was also significantly impaired in Ly49Q-deficient cells in vitro. The inhibitory effect of Ly49Q-deficiency may be explained by the finding that Ly49Q competed for the association of Src-homology domain-2 phosphatase-1 (SHP-1) with paired immunoglobulin-like receptor-B (PIR-B), an ITIM-bearing receptor which negatively regulates osteoclast differentiation. Unexpectedly, Ly49Q deficiency did not lead to impaired osteoclast formation in vivo, suggesting the existence of a compensatory mechanism. This study provides an example in which an ITIM-bearing receptor functions as a positive regulator of osteoclast differentiation.

Paired Immunoglobulin-Like Receptor-B (PIRB) Regulates the Suppressive Function and M1/M2 Differentiation of MDSCs

Paired Immunoglobulin-Like Receptor-B (PIRB) Regulates the Suppressive Function and M1/M2 Differentiation of MDSCs