# Pathogenic role of innate immune cells in lupus nephritis

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $444,467

## Abstract

ABSTRACT
Glomerulonephritis (GN) is a leading cause of morbidity and mortality associated with immune-mediated
diseases, such as systemic lupus erythematosus (SLE). A hallmark of lupus GN is the appearance of auto-
reactive antibodies against nucleic acids which form, together with complement factors, characteristic immune
complex (IC) deposits in kidney glomeruli. These IC are thought to promote disease by two major mechanisms,
i.e. by activation of immune cells via nucleic-acid recognizing Toll-like receptors (TLRs) and by complement-
mediated cytotoxicity. Despite the coherence of this concept, therapeutic progress for this debilitating disease
has been modest, and data shown in this proposal suggest an important pathogenic contribution of innate
immune cells, specifically so-called ‘patrolling monocytes’ (PMo).
 Important advances were made over the last years with respect to the identification of genetic risk factors
for SLE. We had identified one of these genetic risk factors, i.e. TNIP1/ABIN1, independently as TLR signaling
molecule with selective, negative regulatory function for C/EBPβ. This transcription factor controls various
aspects of cell differentiation, including development of mentioned PMo, a cell type with emerging function in
intravascular inflammation. Based on TNIP1’s trait as human SLE risk factor, our lab established Tnip1-/- mice,
which we found to share major characteristics with human SLE, including autoimmunity and severe mesangial-
proliferative GN with IC deposits (PNAS, 2011, Zhou et al).
 In preliminary data we show that GN in Tnip1-/- mice is driven by TLRs, consistent with the current model.
Unexpectedly, however, we also found that GN proceeds independent of IC, but is mediated by innate immune
cells. We identified the critical cell type as mentioned PMo, which accumulate at high numbers in kidney
glomeruli. Strikingly, genetic deletion of PMo prevents kidney damage. As such, we identified a hitherto largely
unsuspected cell type, i.e. PMo, as culprit that mediates GN in Tnip1-/- mice. Based on additional evidence,
including mentioned function of C/EBPβ in PMo development and, importantly, data demonstrating the
presence of PMo in glomeruli of SLE patients, we hypothesize that TLR-driven deregulation of PMo biology
via ABIN1 and C/EBPβ represents a novel key pathogenicity axis in lupus and, possibly, other forms of GN.
 In this project, we will (i) characterize the key steps of deregulated PMo biology, i.e. cell differentiation and
glomerular retention, (ii) define the molecular mechanism that is used by ABIN1 to control C/EBPβ, (iii)
establish a causal link between the C/EBPβ pathway and GN and (iv) identify PMo-specific drug targets and
test current and novel, more selective treatment options for their impact on PMo biology and lupus nephritis.
 Collectively, this project will characterize PMo biology as largely undefined mechanism in lupus GN from
both mechanistic and therapeutic perspectives. Given the conc...

## Key facts

- **NIH application ID:** 9925183
- **Project number:** 5R01AI145877-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** HANS HAECKER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $444,467
- **Award type:** 5
- **Project period:** 2019-05-03 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925183

## Citation

> US National Institutes of Health, RePORTER application 9925183, Pathogenic role of innate immune cells in lupus nephritis (5R01AI145877-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9925183. Licensed CC0.

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