Lupus can impact the nervous system, but researchers aren’t certain how this disease leads to depression, headaches, memory loss, seizures, and other symptoms. We hypothesize that the culprit is a type of microglia, an immune cell in the brain. While this cell population is believed to reduce neuroinflammation, these cells may not function properly in lupus. To test our hypothesis, we will determine whether this type of microglia is abnormal in mice with neuropsychiatric symptoms. We will also test whether returning normally functioning cells to mice can prevent these animals from developing symptoms. Further, we will determine if a population of microglia-like cells in the fluid surrounding the brain of patients with neuropsychiatric symptoms resembles this type of microglia to potentially translate our findings to human disease.

What this study means for people with lupus

“According to some studies, more than 60% of patients with lupus have neuropsychiatric symptoms that result from the disease’s effects on the nervous system, including the brain, but the cause is still not clear. We will test whether these symptoms result from malfunction of a type of immune cell in the brain that may reduce inflammation. Our findings could lead to development of diagnostic markers and, ultimately, safer, more effective therapies to treat these symptoms.”

Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE), including headaches, cognitive dysfunction and psychiatric disorders, affect over 60% of SLE patients, may be among the earliest signs of SLE and often go undetected. Despite the impact of NP-SLE on health-related quality of life and although numerous mechanisms have been proposed, none can solely account for NP-SLE pathogenesis. Microglia are comprised of at least two subsets (CD11chi and CD11clo). While previous studies in neurodegenerative disease models suggest that CD11chi microglia are a regulatory population, relatively little is known about microglial subsets in NP-SLE. Thus, we will examine microglia subsets from both a mouse model of SLE as well as microglia-like cells from cerebrospinal fluid of patients with SLE to dissect their role in disease pathogenesis. We generated the CReCOM (Caspase-8 Removed CD11c-specific Overactive MyD88) mouse, which develops an age-dependent aggressive systemic inflammatory disease reminiscent of SLE that depends on MyD88, a signaling adaptor for most toll-like receptors (TLRs). A major strength of the CReCOM model is its cell-specificity, as CReCOM mice lack caspase-8 in microglia, unlike other models of SLE which have global expression of disease-inducing mutations. Our Preliminary Data demonstrate behavioral deficits in CReCOM mice prior to end-organ damage, corresponding to a marked reduction of the CD11chi regulatory microglial subset. Despite ongoing investigation into CD11chi microglia in neurodegenerative disease models, we will be the first to examine the role of this population in NP-SLE. We hypothesize that NP-SLE-associated pathologies arise from an intrinsic inability to maintain the CD11chi regulatory population of microglia. We will determine whether a microglial-intrinsic defect is sufficient to trigger NP-SLE-like disease by eliminating systemic inflammation via head-shielded reciprocal bone marrow chimeric CReCOM mice. We will test whether the CD11chi microglia suppress NP-SLE-like disease by adoptively transferring healthy CD11chi microglia into CReCOM mice. We will profile CD11chi and CD11clo microglia to detect differences in transcriptional signatures indicative of their subset-specific roles and potential functional deficiencies in NP-SLE-like disease pathogenesis. We will then compare these transcriptional profiles among other models of SLE and microglia-like cells from cerebrospinal fluid of SLE patients with central nervous involvement to potentially identify a common “NP-SLE disease signature.” This information will be invaluable not only for downstream biomarker use but also targeted therapy development. Taken together, we will be the first to examine the role of microglial subsets in the pathogenesis of NP-SLE.