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

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.

Borrelia burgdorferipeptidoglycan is a persistent antigen in patients with Lyme arthritis

“…Half of the mice from each group were randomly selected and euthanized on day 2 or 4 postinjection. Both hind limbs from each euthanized animal were immersion-fixed, decalcified, and stained with hematoxylin-eosin for blinded histopathological evaluation (52).…”

Phagocytic Receptors Activate Syk and Src Signaling during Borrelia burgdorferi Phagocytosis

“…B. burgdorferi internalization can occur through coiling phagocytosis, with the involvement of GTPases such as Cdc42 and Rac1, which lead to actin rearrangement to engulf the bacteria (9,10). The interaction between the bacterium and cell surface receptors such as integrin ␣M␤2 and the Fc␥ receptor results in the formation of F-actin structures that engage the Wiskott-Aldrich family protein and the Arp2/3 complex, leading to the internalization of the pathogen (9,(11)(12)(13)(14)(15). Additionally, B. burgdorferi has been shown to engage other cell surface receptors that also play a role in the internalization of the pathogen, such as the glycosylphosphatidylinositol (GPI)-anchored protein CD14, integrin ␣3␤1, and the scavenger receptor (SR) MARCO (13,14,(16)(17)(18).…”

Selenoprotein K regulation of palmitoylation and calpain cleavage of ASAP2 is required for efficient FcγR-mediated phagocytosis

“…These findings may have implications for diseases related to impaired uptake of immune complexes. Efficient phagocytosis of IgG-coated pathogens is particularly important for clearing infection in diseases driven by extracellular pathogens [35][36][37]. Ineffective clearance of immune complexes can also result in glomerular disease or, possibly, the development of autoimmune diseases like lupus erythematosus [38][39][40].…”