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The Relationship Between Brain Macrophages and Cognitive Dysfunction in Systemic Lupus Erythematosus

Award Number: R01AI170938
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Northwestern University PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving genetic and environmental factors culminating in multiple detrimental comorbidities. One such comorbidity is the onset of what is referred to as CNS lupus (NP-SLE). 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. We published that expression of NP-SLE-specific disease signatures in tissue-resident macrophages in the brain correlates with the severity of behavioral deficits in two NP-SLE models prior to overt systemic disease. Further, our single-cell RNA sequencing (scRNA-seq) data identify homeostatic and disease-associated states in tissue-resident macrophages of aged control and NP-SLE-prone mice. However, the disease-associated macrophage subset in NP-SLE is depleted for genes associated with phagocytosis, which is in contrast to their known phagocytic role in other diseases. We also find that restricted expression of the disease-associated transcriptional program in NP-SLE tissue-resident macrophages corresponds to improved behavioral outcomes in NP-SLE-prone mice following treatment with fingolimod. These discoveries mark the first to implicate this disease-associated tissue- resident macrophage subset as a potentially pathogenic population in NP-SLE, which contrasts with their proposed protective role in the literature. We hypothesize that pathogenic disease-associated tissue- resident macrophages in the brain are crucial for NP-SLE development and targeting this population may represent a new therapeutic avenue for treating NP-SLE. In Aim 1, we will determine whether tissue- resident brain cells or infiltrating immune cells are required for NP-SLE using reciprocal head-shielded bone marrow chimeric mice of WT and NP-SLE-prone donors and recipients. We will test whether blocking transition from the homeostatic state to the disease-associated state via deletion of TREM2 (a critical functional regulator of this population) in tissue-resident macrophages prevents NP-SLE. We will delineate the role that type I interferon (IFN) plays in the development of NP-SLE-like disease by examining the role for the upstream receptor (IFNAR) and downstream signaling protein IFN regulatory factor 5 (IRF5), which have been linked to SLE susceptibility, via deletion of these signaling mediators in tissue-resident macrophages. We identified a cell subset in human cerebrospinal fluid (CSF) that transcriptionally resembles disease-associated tissue-resident macrophages. Moreover, classical monocytes can repopulate a compromised tissue-resident macrophage niche and we see numerical expansion of these cells in NP-SLE models. In Aim 2, we will obtain paired CSF and peripheral blood (PB) from SLE patients with and without NP-SLE for transcriptional profiling of CSF macrophages and PB monocytes to correlate with clinical outcomes. Despite investigation of tissue-resident macrophages in the brain in other disciplines, we will be the first to examine their role in NP-SLE. These data will be invaluable for downstream development of improved diagnostics or targeted therapies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $781,086 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Allergy and Infectious Diseases Research	000	3	6/13/2024	NON-COMPETING CONTINUATION	$781,086
														Subtotal = $781,086

Issue Date FY: 2023 ( Subtotal = $789,602 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Allergy and Infectious Diseases Research	000	2	7/11/2023	NON-COMPETING CONTINUATION	$789,602
														Subtotal = $789,602

Issue Date FY: 2022 ( Subtotal = $799,048 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Allergy and Infectious Diseases Research	000	1	7/5/2022	NEW	$799,048
														Subtotal = $799,048

Grand Total All Awards = $2,369,736

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The Relationship Between Brain Macrophages and Cognitive Dysfunction in Systemic Lupus Erythematosus

Award Number: R01AI170938

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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