# Activation of Macrophages in Human Autoimmune Diseases

> **NIH NIH R01** · HOSPITAL FOR SPECIAL SURGERY · 2024 · $408,129

## Abstract

Macrophages play a key role in the pathogenesis of various autoimmune and rheumatic diseases.
An important mechanism by which activated macrophages contribute to disease pathogenesis is production
of inflammatory cytokines such as TNF, IL-1 and IL-6. These cytokines are canonical NF-B target genes
and validated therapeutic targets. The long term goals of this project are to understand how inflammatory
macrophage activation is regulated, with the associated goal of developing new therapies that selectively
suppress pathogenic macrophage functions, while preserving homeostatic functions and host defense.
 Type I IFNs and IFN- are important regulators of immunity and inflammation. IFNs activate the JAK-
STAT signaling pathway to induce canonical interferon-stimulated genes (ISGs). Expression of IFN target
genes (termed an ‘IFN signature’) is one of the most prominent molecular pathways activated in several
autoimmune diseases including RA, lupus nephritis, and macrophage activation syndrome (MAS) (and
related familial hemophagocytic lymphohistiocytosis (fHLH)). IFNs are clearly pathogenic in monogenic
‘interferonopathies’ and fHLH, where patients are responsive to JAK inhibitors and IFN- blockade. JAK
inhibitors, which target IFNs amongst other cytokines, are effective in RA and are being tested in SLE.
 Although IFNs do not directly activate pathogenic non-ISG inflammatory NF-B target genes such
as TNF, IL1B and IL6, they potentiate induction of these genes by TNF and TLRs. This supports the
possibility that the therapeutic efficacy of IFN blockade or Jak inhibitors may be mediated at least in part by
direct suppression of inflammatory cytokine production in macrophages. In accord with this notion, JAK
inhibitors decrease inflammatory responses and cytokines in RA patients, primed human macrophages, RA
synovial macrophages and tissue explants, and in preclinical models of arthritis and MAS/fHLH.
 In the previous project period we found that IFN-JAK-STAT signaling induces chromatin remodeling
at inflammatory NF-B target genes to make these genes hyper-responsive to inflammatory signals and
resistant to suppression. IFNs also selectively suppressed components of the macrophage response to the
suppressive cytokine IL-10 by deactivating enhancers. These data provide insights into pathways that
connect IFN-JAK-STAT signaling to inflammatory NF-B target genes and support our overarching
hypothesis that IFNs help drive inflammatory non-ISG gene expression via chromatin-based mechanisms.
 In this project we will investigate epigenetic mechanisms by which IFNs drive macrophage activation
and expression of pathogenic NF-B target genes such as TNF, IL1B and IL6, and mechanisms by which
JAK inhibitors suppress these genes. We anticipate that our studies will yield insights that can be used to
develop novel therapeutic strategies to suppress inflammatory responses, and help understand how
epigenetic mechanisms can contribute to poor efficacy of therapies...

## Key facts

- **NIH application ID:** 10823255
- **Project number:** 5R01AI046712-25
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** Lionel B Ivashkiv
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $408,129
- **Award type:** 5
- **Project period:** 2000-03-01 → 2025-08-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823255

## Citation

> US National Institutes of Health, RePORTER application 10823255, Activation of Macrophages in Human Autoimmune Diseases (5R01AI046712-25). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10823255. Licensed CC0.

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