Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers

Abstract

Neutrophils are well characterized as mediators of peripheral tissue damage in lupus, but it remains unclear whether they influence loss of self-tolerance in the adaptive immune compartment. Lupus neutrophils produce elevated levels of factors known to fuel autoantibody production, including interleukin-6 and B cell survival factors, but also reactive oxygen intermediates, which can suppress lymphocyte proliferation. In order to assess whether neutrophils directly influence the progression of auto-reactivity in secondary lymphoid organs (SLO), we characterized the localization and cell-cell contacts of splenic neutrophils at several stages in the progression of disease in the NZB/W murine model of lupus. Neutrophils accumulate in SLO over the course of lupus progression, preferentially localizing near T lymphocytes early in disease and B cells with advanced disease. RNA sequencing reveals that the splenic neutrophil transcriptional program changes significantly over the course of disease, with neutrophil expression of anti-inflammatory mediators peaking during early- and mid-stage disease, and evidence of neutrophil activation with advanced disease. To assess whether neutrophils exert predominantly protective or deleterious effects on loss of B cell self-tolerance in vivo, we depleted neutrophils at different stages of disease. Neutrophil depletion early in lupus resulted in a striking acceleration in the onset of renal disease, SLO germinal center formation, and auto-reactive plasma cell production. In contrast, neutrophil depletion with more advanced disease did not alter SLE progression. These results demonstrate a surprising temporal and context dependent role for neutrophils in restraining auto-reactive B cell activation in lupus.

The role of neutrophils in the pathogenesis of systemic lupus erythematosus

“…Cxcr2 nor Cxcr4-factors mediating neutrophil migration to sites of infection and clearance (respectively)-were differentially expressed (d.n.s) 206 . These chemokine receptor changes are consistent with the changing frequency of neutrophils in the spleen observed in our previously published work 201 . 215 .…”

Recent advances on the crosstalk between neutrophils and B or T lymphocytes

“…Despite the extensive literature supporting a role of neutrophils in driving exaggerated B‐cell responses that can lead to autoimmune and neoplastic disease development, it is important to highlight that evidence that neutrophils may inhibit B‐cell responses is also emerging. For example, neutrophils have been proposed to inhibit IgA production by B cells in a mouse model of sublingual immunization, or to inhibit germinal centre B‐cell formation during the early stages of murine lupus development . Similarly, during the early phases of the humoral response after local Staphylococcus aureus immunization and infection, murine neutrophils have been shown to establish F‐actin‐mediated intercellular contacts with B cells within the lymph nodes, and in turn suppress antibody production via transforming growth factor ‐ β 1 production .…”

Murine lupus is Neutrophil Elastase-independent in the MRL.Faslpr model

“…Animal models of lupus have not supported a pathogenic role for neutrophils in SLE pathogenesis; rather, data has supported a regulatory or neutral role for neutrophils. Antibody mediated depletion of neutrophils early in disease increased autoantibody titers and glomerulonephritis in the NZB/W model [57, 58]. However, neutrophil depletion did not alter autoantibody responses nor renal pathology in established disease [57].…”

“…Antibody mediated depletion of neutrophils early in disease increased autoantibody titers and glomerulonephritis in the NZB/W model [57, 58]. However, neutrophil depletion did not alter autoantibody responses nor renal pathology in established disease [57]. Conditional deletion of neutrophils in mice subjected to the PIL model resulted in increased antinuclear antibody responses [23].…”