RESUMO
Paired Ig-like type 2 receptor (PILR)α inhibitory receptor and its counterpart PILRß activating receptor are coexpressed on myeloid cells. In this article, we report that PILRα, but not PILRß, is elevated in human rheumatoid arthritis synovial tissue and correlates with inflammatory cell infiltration. Pilrα(-/-) mice produce more pathogenic cytokines during inflammation and are prone to enhanced autoimmune arthritis. Correspondingly, engaging PILRα with anti-PILRα mAb ameliorates inflammation in mouse arthritis models and suppresses the production of proinflammatory cytokines. Our studies suggest that PILRα mediates an important inhibitory pathway that can dampen inflammatory responses.
Assuntos
Artrite Experimental/imunologia , Citocinas/imunologia , Inflamação/imunologia , Receptores Imunológicos/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Artrite Experimental/metabolismo , Artrite Experimental/prevenção & controle , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Células Cultivadas , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Células HEK293 , Membro Posterior/efeitos dos fármacos , Membro Posterior/imunologia , Membro Posterior/patologia , Humanos , Imuno-Histoquímica , Inflamação/metabolismo , Inflamação/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Osteoartrite/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma/genética , Transcriptoma/imunologiaRESUMO
Paired immunoglobulin-like receptor (PILR) α is an inhibitory receptor that recognizes several ligands, including mouse CD99, PILR-associating neural protein, and Herpes simplex virus-1 glycoprotein B. The physiological function(s) of interactions between PILRα and its cellular ligands are not well understood, as are the molecular determinants of PILRα/ligand interactions. To address these uncertainties, we sought to identify additional PILRα ligands and further define the molecular basis for PILRα/ligand interactions. Here, we identify two novel PILRα binding partners, neuronal differentiation and proliferation factor-1 (NPDC1), and collectin-12 (COLEC12). We find that sialylated O-glycans on these novel PILRα ligands, and on known PILRα ligands, are compulsory for PILRα binding. Sialylation-dependent ligand recognition is also a property of SIGLEC1, a member of the sialic acid-binding Ig-like lectins. SIGLEC1 Ig domain shares â¼22% sequence identity with PILRα, an identity that includes a conserved arginine localized to position 97 in mouse and human SIGLEC1, position 133 in mouse PILRα and position 126 in human PILRα. We observe that PILRα/ligand interactions require conserved PILRα Arg-133 (mouse) and Arg-126 (human), in correspondence with a previously reported requirement for SIGLEC1 Arg-197 in SIGLEC1/ligand interactions. Homology modeling identifies striking similarities between PILRα and SIGLEC1 ligand binding pockets as well as at least one set of distinctive interactions in the galactoxyl-binding site. Binding studies suggest that PILRα recognizes a complex ligand domain involving both sialic acid and protein motif(s). Thus, PILRα is evolved to engage multiple ligands with common molecular determinants to modulate myeloid cell functions in anatomical settings where PILRα ligands are expressed.
Assuntos
Evolução Molecular , Glicoproteínas de Membrana/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Receptores Imunológicos/metabolismo , Antígeno 12E7 , Sequência de Aminoácidos , Animais , Antígenos CD/química , Antígenos CD/genética , Antígenos CD/metabolismo , Arginina/química , Arginina/genética , Arginina/metabolismo , Sítios de Ligação/genética , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Chlorocebus aethiops , Colectinas/química , Colectinas/genética , Colectinas/metabolismo , Sequência Conservada/genética , Células HEK293 , Humanos , Ligantes , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Dados de Sequência Molecular , Ácido N-Acetilneuramínico/química , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Receptores Imunológicos/química , Receptores Imunológicos/genética , Receptores Depuradores/química , Receptores Depuradores/genética , Receptores Depuradores/metabolismo , Homologia de Sequência de Aminoácidos , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico , Células VeroRESUMO
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several solid and hematological malignancies. ICIs are not only able to produce long and durable responses, but also very well tolerated by patients. There are several approved indications of use of ICIs in treatment of metastatic gastrointestinal malignancies including gastric, esophageal, colorectal and hepatocellular carcinoma. In addition, ICIs can be used in microsatellite instability-high (MSI-H) and high tumor mutational burden (TMB) tumors in chemotherapy-resistant setting. Despite having good efficacy and superior safety profile, ICIs are clinically active in small subset of patients, therefore, there is a huge unmet need to enhance their efficacy and discover new predictive biomarkers. There are several ongoing clinical trials that are exploring the role of ICIs in various gastrointestinal cancers either as single agent or in combination with chemotherapy, radiation therapy, targeted agents or other immunotherapeutic agents. In this review, we discuss the published and ongoing trials for ICIs in gastrointestinal malignancies, including esophageal, gastric cancer, pancreatic, hepatocellular, biliary tract, colorectal and anal cancers. Specifically, we focus on the use of ICIs in each line of therapy and discuss the future directions of these agents in each type of gastrointestinal cancer.