# Regulation of Inflammation by the Fibrinolytic System

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $387,500

## Abstract

Hemostasis and immunity are highly interrelated systems. Dysregulation of hemostasis, thrombosis, and dis-
seminated intravascular coagulation (DIC) are serious complications observed in patients with trauma, sterile
tissue injury, systemic inflammation, and sepsis. This research project focuses on a novel pathway by which
the major intravascular activator of fibrinolysis, tissue-type Plasminogen Activator (tPA), controls innate im-
munity and inflammation. LDL Receptor-related Protein-1 (LRP1) is an endocytic and cell-signaling receptor
for tPA. When LRP1 is deleted conditionally in myeloid cells in mice, the inflammatory response to lipopoly-
saccharide/endotoxin (LPS) is greatly exacerbated. In LRP1-deficient macrophages, NFκB is activated and
expression of pro-inflammatory cytokines is robustly increased. microRNA-155 expression also is increased,
which may sustain inflammation, as is expression of the Serpin fibrinolysis inhibitors, plasminogen activator
inhibitor-1 (PAI-1) and PAI-2, which contribute to a pro-thrombotic state. In macrophages that express LRP1,
different ligands that bind to LRP1 have opposite effects on macrophage phenotype and gene expression, a
phenomenon that we hypothesize reflects ligand-specific recruitment of macrophage co-receptors, including N-
methyl-D-aspartate Receptor. tPA-binding to LRP1 is anti-inflammatory. Enzymatically-inactive tPA (EI-tPA)
blocks the toxicity of LPS in wild-type mice. The anti-inflammatory activity of tPA represents a novel and
unanticipated activity of an FDA-approved drug. The major objective of this grant application is to elucidate the
activity of tPA in inflammation and a novel pathway by which tPA may counteract development of thrombosis in
tissue injury and sepsis. Three specific aims are proposed. In Specific Aim 1, we apply a systems biology
approach to elucidate the anti-inflammatory signaling pathway activated by EI-tPA-binding to LRP1 in macro-
phages. Specific attention will be dedicated to identifying co-receptors, systems of signaling proteins that func-
tion concomitantly to regulate gene expression, and gene products such as SOCS1 and SOCS3, which may
determine whether the effects of tPA on inflammation are sustained. In Specific Aim 2, we test the hypothesis
that tPA suppresses inflammation in response to multiple stimuli by examining two alternative model systems
in mice, lipoteichoic acid challenge and the passive K/BxN serum-transfer arthritis model, in which innate im-
munity is activated by Fc receptors and complement factors. In Specific Aim 3, we test the hypothesis that EI-
tPA may counteract development of pro-thrombotic states in conditions such as trauma and sepsis by
controlling gene expression in macrophages. Proposed experiments in Specific Aim 3 focus on the balance
between plasminogen activators and their inhibitors and on cell-surface receptors that promote plasminogen
activation by tPA. Overall, this project offers an opportunity to further our understa...

## Key facts

- **NIH application ID:** 9913997
- **Project number:** 5R01HL136395-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** STEVEN L. GONIAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2017-04-10 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913997

## Citation

> US National Institutes of Health, RePORTER application 9913997, Regulation of Inflammation by the Fibrinolytic System (5R01HL136395-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9913997. Licensed CC0.

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