Dual role for FcÎ³ receptors in host defense and disease in Borrelia burgdorferi-infected mice

Alexia A Belperron,Carmen J Booth,Nengyin Liu,Linda K Bockenstedt

doi:10.3389/fcimb.2014.00075

Alexia A Belperron, Carmen J Booth + Show 2 more

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https://doi.org/10.3389/fcimb.2014.00075

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Abstract

Arthritis in mice infected with the Lyme disease spirochete, Borrelia burgdorferi, results from the influx of innate immune cells responding to the pathogen in the joint and is influenced in part by mouse genetics. Production of inflammatory cytokines by innate immune cells in vitro is largely mediated by Toll-like receptor (TLR) interaction with Borrelia lipoproteins, yet surprisingly mice deficient in TLR2 or the TLR signaling molecule MyD88 still develop arthritis comparable to that seen in wild type mice after B. burgdorferi infection. These findings suggest that other, MyD88-independent inflammatory pathways can contribute to arthritis expression. Clearance of B. burgdorferi is dependent on the production of specific antibody and phagocytosis of the organism. As Fc receptors (FcγR) are important for IgG-mediated clearance of immune complexes and opsonized particles by phagocytes, we examined the role that FcγR play in host defense and disease in B. burgdorferi-infected mice. B. burgdorferi-infected mice deficient in the Fc receptor common gamma chain (FcεRγ−/− mice) harbored ~10 fold more spirochetes than similarly infected wild type mice, and this was associated with a transient increase in arthritis severity. While the elevated pathogen burdens seen in B. burgdorferi-infected MyD88−/− mice were not affected by concomitant deficiency in FcγR, arthritis was reduced in FcεRγ−/−MyD88−/− mice in comparison to wild type or single knockout mice. Gene expression analysis from infected joints demonstrated that absence of both MyD88 and FcγR lowers mRNA levels of proteins involved in inflammation, including Cxcl1 (KC), Xcr1 (Gpr5), IL-1beta, and C reactive protein. Taken together, our results demonstrate a role for FcγR-mediated immunity in limiting pathogen burden and arthritis in mice during the acute phase of B. burgdorferi infection, and further suggest that this pathway contributes to the arthritis that develops in B. burgdorferi-infected MyD88−/− mice.

Highlights

Lyme disease, due to infection with Borrelia burgdorferi sensu lato spirochetes, is the most common arthropod-borne disease in the northern hemisphere (Kurtenbach et al, 2006)
Our results demonstrate a role for FcγR-mediated immunity in limiting pathogen burden and arthritis in mice during the acute phase of B. burgdorferi infection, and further suggest that this pathway contributes to the arthritis that develops in B. burgdorferi-infected myeloid differentiation primary response gene 88 (MyD88)−/− mice
OspC immune serum alone had no effect. These findings indicate that in the absence of MyD88, macrophages can produce inflammatory cytokines when B. burgdorferi antigens are presented as immune complexes

Summary

Introduction

Due to infection with Borrelia burgdorferi sensu lato spirochetes, is the most common arthropod-borne disease in the northern hemisphere (Kurtenbach et al, 2006). Histopathology of B. burgdorferi-infected mouse tissues reveals a dominance of innate immune cells at sites of inflammation, especially macrophages in the heart and neutrophils in the joints (Barthold et al, 1990, 1992; Ruderman et al, 1995). This pathology develops in the absence of B and T cells, but adaptive immunity is required for the spontaneous, immune-mediated regression of disease (Barthold et al, 1992; McKisic and Barthold, 2000; Bockenstedt et al, 2001)

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