Macrophages play a major role in diseases such as tuberculosis, Leishmania, chronic inflammation, autoimmune diseases, atherosclerosis, obesity, asthma, fibrosis, and cancer, and the disease progression is strongly affected by whether the macrophages are inflammatory M1, profibrotic M2a, or immunoregulatory M2reg. The differentiation of monocytes into M1, M2a, or M2reg has been thought to occur in response to signals released during inflammation or repair. Unexpectedly, a constitutive blood plasma protein called Serum Amyloid P (SAP) induces monocytes to become M2reg macrophages. Signals inducing and produced by M2a macrophages are associated with fibrosis. Injections of SAP in animal models of fibrosis override these signals, induce M2reg differentiation, and inhibit fibrosis. These results suggest that SAP is a constitutive, and at high levels a dominant, regulatory signal in the innate immune system. SAP is a member of the pentraxin family that includes C-polysaccharide reactive protein (CRP) and pentraxin-3 (PTX3). Although CRP has strong sequence and structural similarity to SAP, CRP is a major marker of inflammation, but in some animal models CRP potentiates inflammation, and in other models CRP inhibits inflammation. In an effort to resolve this discrepancy, we found that CRP induces the differentiation of monocytes into Mreg, but induces macrophages to polarize into M1. To gain insight into a fundamental mechanism used to regulate the innate immune system, we propose three specific aims to elucidate the molecular mechanism used by pentraxins to regulate macrophage phenotype.
Our first aim i s to test the hypothesis that pentraxins can have different effects on macrophage differentiation compared to macrophage polarization, and test the hypothesis that ligands that bind pentraxins affect pentraxin signaling. Even though SAP, CRP, and PTX3 have distinct effects on macrophage phenotype, they all bind to Fc? receptors on cells.
Our second aim i s to distinguish between models where SAP activates some Fc? receptors and CRP (and/or PTX3) activates other Fc? receptors, and models where one or more of the pentraxins signals through other receptors to regulate macrophage phenotype.
Our third aim i s to determine the contribution of human Fc? receptors to pentraxin regulation of human macrophage phenotype. We will then use this information to screen for compounds that block the binding of a given pentraxin to a given Fc? receptor, and thus in the presence of the pentraxin, alter macrophage phenotype. Together, this work will help to elucidate a novel mechanism used by the innate immune system to regulate macrophage differentiation, and may lead to new therapies for macrophage-associated diseases.

Public Health Relevance

Immune system cells called macrophages can contribute to a wide variety of diseases such as tuberculosis, Leishmania, chronic inflammation, autoimmune diseases, atherosclerosis, obesity, asthma, fibrosis, and cancer by either persistently attacking the body, or by not attacking an infection. Three related proteins are signals that regulate macrophages; one calms macrophages, the other two are thought to have an inflammatory effect. We propose to determine how these proteins regulate macrophages, with the goal of using this information to develop new therapeutics for macrophage-associated diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Innate Immunity and Inflammation Study Section (III)
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Harabin, Andrea L
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Texas A&M University
Schools of Arts and Sciences
College Station
United States
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Pilling, Darrell; Gomer, Richard H (2018) The Development of Serum Amyloid P as a Possible Therapeutic. Front Immunol 9:2328
White, Michael J V; Chinea, Luis E; Pilling, Darrell et al. (2018) Protease activated-receptor 2 is necessary for neutrophil chemorepulsion induced by trypsin, tryptase, or dipeptidyl peptidase IV. J Leukoc Biol 103:119-128
Chen, Wensheng; Pilling, Darrell; Gomer, Richard H (2017) Dietary NaCl affects bleomycin-induced lung fibrosis in mice. Exp Lung Res 43:395-406
Xiang, Wang; Cox, Nehemiah; Gomer, Richard H (2017) Identification of compounds that decrease numbers of Mycobacteria in human macrophages in the presence of serum amyloid P. J Leukoc Biol 102:857-869
Karhadkar, Tejas R; Pilling, Darrell; Cox, Nehemiah et al. (2017) Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model. Sci Rep 7:15069
Pilling, Darrell; Galvis-Carvajal, Elkin; Karhadkar, Tejas R et al. (2017) Monocyte differentiation and macrophage priming are regulated differentially by pentraxins and their ligands. BMC Immunol 18:30
Herlihy, Sarah E; Starke, Hannah E; Lopez-Anton, Melisa et al. (2016) Peritoneal Dialysis Fluid and Some of Its Components Potentiate Fibrocyte Differentiation. Perit Dial Int 36:367-73
White, Michael J V; Gomer, Richard H (2015) Trypsin, Tryptase, and Thrombin Polarize Macrophages towards a Pro-Fibrotic M2a Phenotype. PLoS One 10:e0138748
White, Michael J V; Roife, David; Gomer, Richard H (2015) Galectin-3 Binding Protein Secreted by Breast Cancer Cells Inhibits Monocyte-Derived Fibrocyte Differentiation. J Immunol 195:1858-67
Cox, Nehemiah; Pilling, Darrell; Gomer, Richard H (2015) DC-SIGN activation mediates the differential effects of SAP and CRP on the innate immune system and inhibits fibrosis in mice. Proc Natl Acad Sci U S A 112:8385-90

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