Differential Modulation of Human M1 and M2 Macrophage Activity by ICOS-Mediated ICOSL Triggering

Activated T cells express the inducible T-cell co-stimulator (ICOS) that, upon binding to its ubiquitously expressed ligand (ICOSL), regulates the immune response and tissue repair. We sought to determine the effect of ICOS:ICOSL interaction on human M1 and M2 macrophages. M1 and M2 macrophages were polarized from monocyte-derived macrophages, and the effect of a soluble recombinant form of ICOS (ICOS-CH3) was assessed on cytokine production and cell migration. We show that ICOS-CH3 treatment increased the secretion of CCL3 and CCL4 in resting M1 and M2 cells. In LPS-treated M1 cells, ICOS-CH3 inhibited the secretion of TNF-α, IL-6, IL-10 and CCL4, while it increased that of IL-23. In contrast, M2 cells treated with LPS + IL4 displayed enhanced secretion of IL-6, IL-10, CCL3 and CCL4. In CCL7- or osteopontin-treated M1 cells, ICOS-CH3 boosted the migration rate of M1 cells while it decreased that of M2 cells. Finally, β-Pix expression was upregulated in M1 cells and downregulated in M2 cells by treatment with ICOS-CH3. These findings suggest that ICOSL activation modulates the activity of human M1 and M2 cells, thereby eliciting an overall anti-inflammatory effect consistent with its role in promoting tissue repair.

[1]  U. Dianzani,et al.  ICOS-Fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsis , 2022, Frontiers in Immunology.

[2]  U. Dianzani,et al.  ICOSL Stimulation by ICOS-Fc Accelerates Cutaneous Wound Healing In Vivo , 2022, International journal of molecular sciences.

[3]  U. Dianzani,et al.  G protein-coupled receptor 21 in macrophages: An in vitro study. , 2022, European journal of pharmacology.

[4]  A. Chiocchetti,et al.  Inducible T‐cell co‐stimulator (ICOS) and ICOS ligand are novel players in the multiple‐myeloma microenvironment , 2021, British journal of haematology.

[5]  U. Dianzani,et al.  Inducible T-Cell Costimulator Mediates Lymphocyte/Macrophage Interactions During Liver Repair , 2021, Frontiers in Immunology.

[6]  G. Cappellano,et al.  Osteopontin binds ICOSL promoting tumor metastasis , 2020, Communications biology.

[7]  G. Cappellano,et al.  Immunotherapy of experimental melanoma with ICOS-Fc loaded in biocompatible and biodegradable nanoparticles. , 2020, Journal of controlled release : official journal of the Controlled Release Society.

[8]  V. Yakubenko,et al.  Distinct Migratory Properties of M1, M2, and Resident Macrophages Are Regulated by αDβ2 and αMβ2 Integrin-Mediated Adhesion , 2018, Front. Immunol..

[9]  J. T. Afshari,et al.  Macrophage plasticity, polarization, and function in health and disease , 2018, Journal of cellular physiology.

[10]  Ling Zhao,et al.  Inflammatory responses and inflammation-associated diseases in organs , 2015, Oncotarget.

[11]  A. Chiocchetti,et al.  ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Vivo , 2016, The Journal of Immunology.

[12]  Rebecca Liu,et al.  IL-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium , 2016, The Journal of Immunology.

[13]  G. Cappellano,et al.  Thrombin Cleavage of Osteopontin Modulates Its Activities in Human Cells In Vitro and Mouse Experimental Autoimmune Encephalomyelitis In Vivo , 2016, Journal of immunology research.

[14]  E. Orilieri,et al.  B7h Triggering Inhibits the Migration of Tumor Cell Lines , 2014, The Journal of Immunology.

[15]  Judy H. Cho,et al.  Pattern recognition receptor signaling in human dendritic cells is enhanced by ICOS ligand and modulated by the Crohn's disease ICOSLG risk allele. , 2014, Immunity.

[16]  Michael Q. Ding,et al.  Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli , 2014, PloS one.

[17]  H. D. de Vries,et al.  Macrophages migrate in an activation-dependent manner to chemokines involved in neuroinflammation , 2014, Journal of Neuroinflammation.

[18]  Katherine A. Gallagher,et al.  Cytokine Induced Phenotypic and Epigenetic Signatures Are Key to Establishing Specific Macrophage Phenotypes , 2013, PloS one.

[19]  E. Orilieri,et al.  Differential induction of IL-17, IL-10, and IL-9 in human T helper cells by B7h and B7.1. , 2013, Cytokine.

[20]  O. Fardel,et al.  Polarization profiles of human M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin. , 2013, Cellular immunology.

[21]  A. Chiocchetti,et al.  Triggering of B7h by the inducible costimulator modulates maturation and migration of monocyte-derived dendritic cells , 2012 .

[22]  M. Fujimoto,et al.  Inducible costimulator (ICOS) and ICOS ligand signaling has pivotal roles in skin wound healing via cytokine production. , 2011, The American journal of pathology.

[23]  Peter J. Morrison,et al.  Interleukin‐23 and T helper 17‐type responses in intestinal inflammation: from cytokines to T‐cell plasticity , 2011, Immunology.

[24]  A. Chiocchetti,et al.  B7h Triggering Inhibits Umbilical Vascular Endothelial Cell Adhesiveness to Tumor Cell Lines and Polymorphonuclear Cells , 2010, The Journal of Immunology.

[25]  P. Zhang,et al.  Reverse signaling using an inducible costimulator to enhance immunogenic function of dendritic cells , 2009, Cellular and Molecular Life Sciences.

[26]  B. Grimbacher,et al.  The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency , 2009, Immunological reviews.

[27]  V. Kuchroo,et al.  The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells , 2009, Nature Immunology.

[28]  M. Ferretti,et al.  ICOS cooperates with CD28, IL-2, and IFN-gamma and modulates activation of human naïve CD4+ T cells. , 2006, European journal of immunology.

[29]  R. Nurieva.  Regulation of immune and autoimmune responses by ICOS-B7h interaction. , 2005, Clinical immunology.

[30]  U. Dianzani,et al.  A co-stimulatory molecule on activated T cells, H4/ICOS, delivers specific signals in T(h) cells and regulates their responses. , 2002, International immunology.

[31]  G. Freeman,et al.  The B7–CD28 superfamily , 2002, Nature Reviews Immunology.

[32]  Hennie R. Hoogenboom,et al.  In vitro characterisation of a monovalent and bivalent form of a fully human anti Ep-CAM phage antibody , 2001, Cancer Immunology, Immunotherapy.