# Regulation, function and localization of monocytes in autoimmune tissues

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $498,353

## Abstract

A central challenge in autoimmunity is to discover the cells and pathways that drive pathological immune
responses in humans. Previous studies of human samples were limited by low-dimensional single cell methods
or high-dimensional bulk methods confounded by cell mixtures. By sequencing RNA of thousands of single cells
from lupus nephritis kidneys, we found 21 unique immune cell states, many of which were also found in synovial
tissue of RA patients. In Project 2, we will focus on 3 monocyte states that we observe in lupus nephritis kidneys,
which likely arise from patrolling blood monocytes that enter the kidney. While these monocytes share expressed
genes with the previously described M1/M2 spectrum of monocyte states, they express distinct functional
modules and do not map directly to those states. To better understand these disease-associated monocyte
states, we will perform experiments to address three hypotheses. First, we hypothesize that monocyte
inflammation, phagocytosis, and tissue repair programs in lupus nephritis kidneys are regulated by fibroblasts
and tissue-derived factors. With Project 3, we will co-culture primary monocytes with activated/inflammatory
fibroblasts together with known local pathogenic factors and determine changes in cellular functions, including
phagocytosis, cytokine secretion, endothelial extravasation, T/B cell activation (with Project 1) and other
functions. Preliminary data show that fibroblasts and a proposed pathogenic factor, necrotic cells, strongly induce
monocyte differentiation. Second, we hypothesize that TFs expressed in lupus monocytes will induce
differentiation and expression of disease-associated gene inflammation and tissue repair programs. We will
overexpress candidate TFs (based on their expression and genetic association with lupus) in monocytes and
assess inflammation, phagocytosis, and differentiation. Preliminary studies show that the TF overexpression is
feasible, impacts differentiation, and if successful, would allow reliable in vitro generation of differentiated
monocytes for functional studies. Third, to address monocyte roles in lupus nephritis kidneys, we hypothesize
that the proximity of monocytes, fibroblasts and tissue lesions, along with expression of fibroblast-induced
monocyte gene programs, will reflect cell-cell interactions and functions of monocytes in patient kidneys. Using
automated staining, microscopy and image analysis (with the Computational Systems Immunology Core) of
kidney sections from up to 205 clinically-annotated lupus nephritis patients, we will visualize and assess co-
localization of monocytes, fibroblasts, tissue structures/lesions. Preliminary data shows close contacts between
monocytes and fibroblasts and feasibility of scaling our imaging studies to the full cohort. By building on a more
accurate definition of monocytes in human lupus nephritis kidneys, developing methods to study them in vitro
and in human tissues, we will define the origin, differen...

## Key facts

- **NIH application ID:** 10427146
- **Project number:** 5P01AI148102-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Nir Hacohen
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $498,353
- **Award type:** 5
- **Project period:** 2021-06-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427146

## Citation

> US National Institutes of Health, RePORTER application 10427146, Regulation, function and localization of monocytes in autoimmune tissues (5P01AI148102-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10427146. Licensed CC0.

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