Contribution of dysregulated granulopoiesis to SLE pathogenesis

An infection is an emergency for the body, and the immune system can generate more neutrophils to fight invading bacteria. But this emergency response may also occur in lupus, producing large numbers of immature neutrophils that may be harmful. Our research will examine whether the emergency mechanism for making neutrophils is activated in lupus. We will also test whether immature neutrophils promote inflammation and thus could worsen flares. Identifying how the immune system controls production of the immature cells could provide clues about how to reduce their numbers in lupus.

What this study means for people with lupus

“We hypothesize that an immature form of  immune cells known as neutrophils make lupus flares worse. We will investigate how the immune system produces these cells and whether they stimulate inflammation in lupus. The research could uncover new drug targets for blocking these harmful neutrophils.”

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by autoantibody production and periods of elevated and suppressed disease activity. The mechanisms that lead to increased disease activity, also called as a flare, are not clear. Recently neutrophils have gained attention as one of the players in pathophysiology of SLE, however, their precise role is not understood. SLE patients have increased numbers of low density granulocytes (LDG), but the LDG regulated mechanisms that modulate SLE pathogenesis are not well understood. This proposal aims to fill these knowledge gaps. Our data show that SLE patients with elevated disease activity (active SLE patients) have increased numbers of immature neutrophils in the LDG fraction compared to inactive patients. These numbers correlate to SLE disease activity index as well as cytokines involved in granulopoiesis. Interestingly, we saw a similar increase in immature neutrophils in autoantibody positive, but not negative, lupus-prone mice. Neutrophils from SLE patients also showed reduced levels of negative regulators of granulopoiesis. We hypothesize that increase in granulopoiesis inducing cytokines with increasing SLE disease activity induces emergency granulopoiesis and allows for the egress of pro-inflammatory immature neutrophils that further exacerbate the autoimmune response, thus forming a vicious cycle. In the first aim of this proposal, we will determine if immature neutrophils in SLE patients and lupus-prone mice are hyper-responsive to stimulation and produce pro-inflammatory cytokines. In the second aim, we will determine if the cytokines that correlate with immature neutrophil numbers and disease progression in humans promote emergency granulopoiesis, accumulation of pro-inflammatory immature neutrophils, and exacerbation of disease in lupus-prone mice. Finally, we will determine whether downregulation granulopoiesis regulating microRNA result in increased immature and pro-inflammatory neutrophils in SLE patients and mice. We propose granulopoiesis as a pathogenic mechanism in SLE flare. These studies will lead to identification of a possible inflammatory subset of neutrophils and associated pathways, advancing the field of lupus research, and will lead to newer neutrophil specific targets for therapeutic intervention in lupus.