Differential acquired immune responsiveness to bacterial lipoproteins in Lyme disease‐resistant and ‐susceptible mouse strains

Abstract

We investigated the effect of Borrelia burgdorferi lipoproteins (outer surface protein A) and the synthetic lipohexapeptide tripalmitoyl-S-glyceryl-Cys-Ser-4(Lys) (Pam 3 -Cys) on isolated lymph node (LN) cells from Lyme disease-susceptible (C3H/HeJ) and -resistant (C57BL/6J) mice. Mice were either infected with B. burgdorferi for 1 week or left uninfected. Lipoproteinstimulated LN cells from infected C3H/HeJ mice produced significantly higher levels of the inflammatory cytokines IL-6 and IFN-+ than did cells from C57BL/6J mice. Cells from uninfected mice did not respond. No TNF- § or IL-1 g were produced by LN cells from infected mice of either strain in response to lipoprotein or B. burgdorferi spirochetes. Unlike with IL-6 or IFN-+ , LN cells from either strain failed to produce IL-10 in response to lipoproteins. However, the LN cells were able to produce this cytokine in response to B. burgdorferi spirochetes or after incubation with phorbol-12-myristate-13-acetate/ionomycin, anti-CD3 antibody alone or anti-CD3 combined with anti-CD28 antibodies. Addition of exogenous IL-10 to lipopeptide-stimulated cultures significantly reduced IFN-+ and IL-6 production in a dosedependent fashion. This inhibition was more effective with cells from disease-resistant C57BL/6J mice than with cells from disease-susceptible C3H/HeJ mice. The proclivity to disease of the C3H/HeJ mouse could be simultaneously based on the phenomena of enhanced inflammatory responsiveness to lipoproteins and diminished ability to respond to IL-10. An investigation of the determinants of these two phenomena could be used as a blueprint to elucidate the pathogenesis of Lyme disease in humans.

Interleukin-10 Anti-Inflammatory Response toBorrelia burgdorferi, the Agent of Lyme Disease: a Possible Role for Suppressors of Cytokine Signaling 1 and 3

“…More importantly, IL-10 has proved to be a key cytokine in regulating inflammatory responses in Lyme disease by controlling the production and function of various proinflammatory cytokines. We (22,23,26,45) and others (8,25,31,42,51,66) have reported on experiments in vitro showing that in response to B. burgdorferi and its lipoproteins, IL-10 dampens proinflammatory responses of cells that are involved in innate and acquired immunity. Additionally, we (F. Ganapamo, V. A. Dennis, and M. T. Philipp, unpublished data) as well as others (8) have observed that bone marrow-derived macrophages from C57BL/6J (C57) mice, which are Lyme disease resistant, produce higher levels of IL-10 (and lower levels of IL-6, IL-12, and TNF-␣) than do macrophages from the disease-susceptible C3H/HeN (C3H) mice in response to B. burgdorferi or its lipoproteins.…”

“…Spirochetal persistence in the tissues has been associated with severe pathology (14,21,65) and both acute and chronic inflammatory conditions (50,59). Numerous studies have shown that B. burgdorferi and its lipoproteins can induce in a variety of cell types the release of proinflammatory cytokines, such as interleukin-1␣ (IL-1␣) (10), IL-1␤ (45), 23,45,54,55,64), IL-8 (10), IL-12 (30,45,58), tumor necrosis factor alpha (TNF-␣) (8,45,53,54,55,58,64), gamma interferon (IFN-␥) (22,23,24), IL-17 (35), granulocyte-macrophage colony-stimulating factor (GM-CSF) (67), and IL-18 (30). These cytokines may contribute to tissue inflammation and damage.…”

Seroprevalence of Coxiella burnetii among domestic ruminants and horses in Poland

“…Sensitive strains of laboratory mice include SCID, C3H, and SWR mice (Barthold et al, 1990(Barthold et al, , 1999Schaible et al, 1990;Zeidner et al, 1997). Previous studies have proven that the C57DL/6 strain, DBA/ 2J, and the BALB/c are non-sensitive to borreliae (Zeidner et al, 1997;Brown and Reiner, 1998;Ma et al, 1998;Brown et al, 2003;Ganapamo et al, 2003). However, recent studies consider BALB/c mice susceptible to B. afzelii infection (Tonetti et al, 2015;Jacquet et al, 2016).…”

Interleukin-10 (IL-10) Inhibits Borrelia burgdorferi-Induced IL-17 Production and Attenuates IL-17-Mediated Lyme Arthritis

“…In contrast, the effects of IL-10 on IL-17 production were more pronounced after 1 week of infection. Borrelial infection in the presence or absence of IL-10 may be associated with an inverse response of various inflammatory cytokines, including not only tumor necrosis factor alpha and IFN-␥ (3,4,(28)(29)(30)(46)(47)(48)(49)(50)(51) but also IL-17. If a certain threshold of immunosuppression by IL-10 is not achieved, a significant, multifaceted inflammatory response may ensue.…”

“…In addition, B. burgdorferi induces production of the anti-inflammatory cytokine interleukin-10 (IL-10) early after stimulation of host cells (2)(3)(4), suggesting a possible mechanism of facilitating infection in the host. IL-10 also plays a central role in regulating the immune response during sustained infection with B. burgdorferi.…”