Emerging Roles for G-protein Coupled Receptors in Development and Activation of Macrophages

Wang, Xinming; Iyer, Abishek; Lyons, A. Bruce; Korner, Heinrich; Wei, Wei

doi:10.3389/fimmu.2019.02031

Cited by 26 publications

(26 citation statements)

References 151 publications

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“…The ´green´ module was also enriched for genes in the Reactome pathway ‘Class A/1 (Rhodopsin-like receptors)’ ( Supplementary Figure S8 ). Rhodopsin-like receptors are a large group of G-protein coupled receptors and include the chemokine receptors [ 41 ]. The Reactome pathways ‘Class A/1 (Rhodopsin-like receptors)’ and ‘Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell’ include a number of genes encoding cell adhesion molecules, chemokines, and receptors that are important in modifying the response of lymphoid cells to the tumor, which highlights these genes for further evaluation.…”

Section: Resultsmentioning

confidence: 99%

Analysis of Intra-Tumoral Macrophages and T Cells in Non-Small Cell Lung Cancer (NSCLC) Indicates a Role for Immune Checkpoint and CD200-CD200R Interactions

Tøndell

Subbannayya

Wahl

et al. 2021

Cancers

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Non-small cell lung carcinoma (NSCLC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related deaths. Immunotherapy with immune checkpoint inhibitors shows beneficial responses, but only in a proportion of patients. To improve immunotherapy in NSCLC, we need to map the immune checkpoints that contribute immunosuppression in NSCLC-associated immune cells and to identify novel pathways that regulate immunosuppression. Here, we investigated the gene expression profiles of intra-tumoral immune cells isolated from NSCLC patients and compared them to the expression profiles of their counterparts in adjacent healthy tissue. Transcriptome analysis was performed on macrophages, CD4+ and CD8+ T cells. The data was subjected to Gene Ontology (GO) term enrichment and weighted correlation network analysis in order to identify mediators of immunosuppression in the tumor microenvironment in NSCLC. Immune cells from NSCLC revealed a consistent differential expression of genes involved in interactions between myeloid cells and lymphocytes. We further identified several immunosuppressive molecules and pathways that may be activated in tumor-associated macrophages in NSCLC. Importantly, we report novel data on immune cell expression of the newly described CD200/CD200R1 pathway, and the leukocyte immunoglobulin-like receptors (LILRs), which may represent novel innate immune checkpoints, dampening the anti-tumor T cell immune response in NSCLC. Our study substantiates the importance of tumor-associated macrophages as a mediator of immunosuppression and a promising target for immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Analysis of Intra-Tumoral Macrophages and T Cells in Non-Small Cell Lung Cancer (NSCLC) Indicates a Role for Immune Checkpoint and CD200-CD200R Interactions

Tøndell

Subbannayya

Wahl

et al. 2021

Cancers

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“…Prior work has eluded that balanced immune responses are brought about when the immune system dynamically responds to cues from both host and pathogen across multiple scales (47) By elucidating the role of GIV, a non-canonical GEF for Gαi proteins, our findings also provide insights into a hitherto unknown mechanism of signal integration and convergence between TLRs and heterotrimeric G proteins. The role of the G-protein coupled receptor (GPCR)→G protein→cAMP signaling cascade in macrophage differentiation and in shaping macrophage responses to pathogens and injury-related danger molecules is well recognized (48).…”

Section: Resultsmentioning

confidence: 99%

TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin

Swanson

Katkar

Tam

et al. 2020

Preprint

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Sensing of pathogens by Toll-like receptor 4 (TLR4) induces an inflammatory response; controlled responses confer immunity but uncontrolled responses cause harm. Here we define how a multi-modular scaffold, GIV (a.k.a Girdin) titrates such inflammatory response in macrophages. Upon challenge with either live microbes or microbe-derived lipopolysaccharides (LPS, a ligand for TLR4), macrophages with GIV mount a more tolerant (hypo-reactive) transcriptional response and suppress pro-inflammatory cytokines and signaling pathways (i.e., NFkB and CREB) downstream of TLR4 compared to their GIV-depleted counterparts. Myeloid-specific gene depletion studies confirmed that the presence of GIV ameliorates DSS-induced colitis and sepsis-induced death. The anti-inflammatory actions of GIV are mediated via its C-terminally located TIR-like BB-loop (TILL)-motif which binds the cytoplasmic TIR-modules of TLR4 in a manner that precludes receptor dimerization; the latter is a pre-requisite for pro-inflammatory signaling. Binding of GIV’s TILL motif to other TIR modules inhibits pro-inflammatory signaling via other TLRs, suggesting a convergent paradigm for fine-tuning macrophage inflammatory responses.SignificanceTo ensure immunity, and yet limit pathology, inflammatory responses must be confined within the proverbial ‘Goldilocks zone’. TLR4 is the prototypical sensor that orchestrates inflammatory responses through a series of well characterized downstream cascades. How TLR4 signals are confined remain incompletely understood. Using trans-scale approaches ranging from disease modeling in live animals, through cell-based interventional studies, to structure-guided biochemical studies that offer an atomic-level resolution, this study unravels the existence of a ‘brake’ within the TLR4 signaling cascade, i.e., GIV; the latter is a prototypical member of an emerging class of scaffold proteins. By showing that GIV uses conserved mechanisms to impact multi-TLR signaling, this work unravels a multi-scale point of convergence of immune signaling of broader impact beyond TLR4.

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“…The present results suggest that both protein families might cooperate to fight infection by shared convergent mechanisms of RNA processing. Indeed, recent work highlighted the importance of coordinated signalling pathways that mediate the macrophage defence mechanism against infection [97,98].…”

Section: Discussionmentioning

confidence: 99%

Human RNase3 immune modulation by catalytic-dependent and independent modes in a macrophage-cell line infection model

Wei

Prats-Ejarque

et al. 2020

Cell. Mol. Life Sci.

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The human RNase3 is a member of the RNaseA superfamily involved in host immunity. RNase3 is expressed by leukocytes and shows broad-spectrum antimicrobial activity. Together with a direct antimicrobial action, RNase3 exhibits immunomodulatory properties. Here, we have analysed the transcriptome of macrophages exposed to the wild-type protein and a catalytic-defective mutant (RNase3-H15A). The analysis of differently expressed genes (DEGs) in treated THP1-derived macrophages highlighted a common pro-inflammatory “core-response” independent of the protein ribonucleolytic activity. Network analysis identified the epidermal growth factor receptor (EGFR) as the main central regulatory protein. Expression of selected DEGs and MAPK phosphorylation were inhibited by an anti-EGFR antibody. Structural analysis suggested that RNase3 activates the EGFR pathway by direct interaction with the receptor. Besides, we identified a subset of DEGs related to the protein ribonucleolytic activity, characteristic of virus infection response. Transcriptome analysis revealed an early pro-inflammatory response, not associated to the protein catalytic activity, followed by a late activation in a ribonucleolytic-dependent manner. Next, we demonstrated that overexpression of macrophage endogenous RNase3 protects the cells against infection by Mycobacterium aurum and the human respiratory syncytial virus. Comparison of cell infection profiles in the presence of Erlotinib, an EGFR inhibitor, revealed that the receptor activation is required for the antibacterial but not for the antiviral protein action. Moreover, the DEGs related and unrelated to the protein catalytic activity are associated to the immune response to bacterial and viral infection, respectively. We conclude that RNase3 modulates the macrophage defence against infection in both catalytic-dependent and independent manners.

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Emerging Roles for G-protein Coupled Receptors in Development and Activation of Macrophages

Cited by 26 publications

References 151 publications

Analysis of Intra-Tumoral Macrophages and T Cells in Non-Small Cell Lung Cancer (NSCLC) Indicates a Role for Immune Checkpoint and CD200-CD200R Interactions

Analysis of Intra-Tumoral Macrophages and T Cells in Non-Small Cell Lung Cancer (NSCLC) Indicates a Role for Immune Checkpoint and CD200-CD200R Interactions

TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin

Human RNase3 immune modulation by catalytic-dependent and independent modes in a macrophage-cell line infection model

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