IL-10 regulation of lupus in the NZM2410 murine model

Abstract

Multiple studies have reported high levels of IL-10 in SLE patients and in murine models of lupus. IL-10 is a regulatory cytokine mainly produced by B cells, which use this cytokine to support their proliferation, and by myeloid cells, which use IL-10 to reduce proinflammatory responses. IL-10 is also produced by a subset of CD4+ T regulatory cells. Various manipulations of IL-10 levels with repeated administrations of anti-IL-10 neutralizing antibodies, genetic ablation or injections of recombinant cytokine have shown contradictory results, which is likely to reflect the opposite effects of this cytokine on the two major effector arms of lupus pathologenesis, namely B cells and inflammation. We have investigated the role of IL-10 in a novel congenic model of lupus, B6.Sle1.Sle2.Sle3 (B6.TC), which consists of the three NZM2410-derived SLE susceptibility loci combined on a C57BL/6 background. We first investigated in this model the source of elevated IL-10 and shown that it results from a larger number of CD4+ T cells producing the cytokine, and from a greatly increased B1-a cell pool, which is the main IL-10 producing compartment. We have then used AAV-mediated skeletal muscle gene delivery to overexpress IL-10 in young B6.TC mice and follow disease marker expression up to 7 months of age. We show here that continuous overexpression of low levels of IL-10 significantly delayed antinuclear auto-antibody production and decreased clinical nephritis. B cell phenotypes were largely unaffected, while T-cell activation was significantly reduced. This highlighted the pivotal role played by T-cell activation in this model, and suggested that this pathway could be effectively targeted for therapeutic interventions. These results also reinforce the notion that IL-10 exerts multiple functions and commend caution in equating high levels of IL-10 and increased pathogenesis in systemic autoimmunity.

B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice

“…IL-10 also clearly limits the expansion of hyperactivated myeloid cells producing elevated amounts of proinflammatory cytokines that promote the establishment of pathogenic cross-talk between myeloid cells and T cells (14). Our data are consistent with a protective role of IL-10 observed in other mouse models of SLE-like disease, including IL-10-deficient MLR-Fas lpr mice (45) and IL-10-overexpressing B6.Sle1.Sle2.Sle3 mice (46), but disagree with the pathogenic role of IL-10 demonstrated after administration of neutralizing anti-IL-10 antibody in New Zealand Black/White F1 hybrid mice (47). Several hypotheses attempted to explain these discrepancies, including the possibility that the positive and negative regulatory effects of IL-10 might differ depending on the timing of IL-10 overproduction, the levels of expression, or the cell source of IL-10 (45, 46).…”

Cytokines and Systemic Lupus Erythematosus

“…Interestingly, other study has recently been shown that the presence of immune complexes and IFN a cytokine implicated in the pathogenesis of SLE, decreases the capacity of IL-10 to suppress inflammation, limiting therefore the anti-inflammatory effect of this cytokine (Yuan et al, 2011). These results reinforce the notion that IL-10 exerts multiple functions and we must be cautious in equating high levels of IL-10 and increased pathogenesis in systemic autoimmunity (Blenman et al, 2006).…”

“…However, the specificity of these findings is unclear. A recent study that investigated the role of IL-10 in a novel congenic model of lupus, B6.Sle1.Sle2.Sle3 (B6.TC) showed, that although B6.TC mice produced higher IL-10 levels that nonautoimmune control mice, an overexpression of IL-10 decreased T-cell activation, auto-antibody production and autoimmune pathogenesis (Blenman et al, 2006). Interestingly, other study has recently been shown that the presence of immune complexes and IFN a cytokine implicated in the pathogenesis of SLE, decreases the capacity of IL-10 to suppress inflammation, limiting therefore the anti-inflammatory effect of this cytokine (Yuan et al, 2011).…”

Multiple Mechanisms of Immune Suppression by B Lymphocytes

“…It is also possible that functional immune-suppressive B cells may contribute to autoimmune pathogenesis in some cases. Elevated IL-10 levels have been linked to increased pathogenesis in SLE in patients and mouse models, yet B cell-specific IL-10 production and T-cell suppression was impaired in a cohort of SLE patients (44,(157)(158)(159). These seemingly conflicting results highlight the need for a deeper understanding not only of the direct functions of suppressive B cells but also their interactions with other effector and regulatory cell populations.…”