# Regulation of susceptibility and severity of inflammatory diseases of the central nervous system by novel innate immune signaling pathways in human myeloid cells

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2022 · —

## Abstract

Individual variation in inflammatory responses regulates onset and severity of multiple sclerosis (MS) and other
types of brain injury. Initiation, amplification, and resolution of these inflammatory responses occur in part
through innate immune signaling mediated by macrophages and related immune cells. This laboratory has
discovered novel innate immune signaling pathways in human macrophages that are regulated by intracellular
splice variants of voltage-gated sodium channels. These channels regulate pattern recognition of dsRNA,
intracellular signaling, vesicular trafficking, and transcription of anti-viral genes. In a mouse model of MS,
expression of one of these channels, human macrophage SCN5A, in mouse macrophages reduced disease
severity and enhanced tissue repair. Recently published work demonstrates that a newly discovered channel
variant, human macrophage SCN10A, acts in a synergistic manner with SCN5A to regulate RNA processing of
a transcript that encodes a DNA repair protein, PPP1R10. New preliminary data demonstrate individual
variation in regulation of PPP1R10 expression. New data also reveal that SCN10A localizes to mitochondria
during cellular injury and regulates ATP production. The objective of this revised proposal is to characterize
these innate immune signaling mechanisms in human cells and an animal model. The central hypothesis is
that human macrophage SCN10A and SCN5A prevent cell and tissue injury through enhancement of DNA
repair and maintenance of cellular bioenergetics. This hypothesis will be assessed in three aims: 1) Analyze
how human macrophage channel variants regulate PPP1R10 protein expression, 2) Determine how the human
macrophage channel variants regulate mitochondrial function, and 3) Characterize how macrophage SN10A
and SCN5A prevent tissue injury. For Aim 1, the proposed model is that endogenous signals of cellular injury
activate human macrophage SCN10A and SCN5A to initiate a calcium-dependent nuclear signaling pathway
that regulates expression of the DNA repair protein PPP1R10. It is hypothesized that individual variation in this
pathway increases the risk of tissue injury in inflammatory diseases such as MS. For Aim 2, it is proposed that
human macrophage SCN10A localizes to mitochondria during cellular injury to transiently increase
mitochondrial ATP production. It is also hypothesized that SCN10A and SCN5A regulate mitophagy, a cellular
protective mechanism. For Aim 3, it is postulated that macrophages that express human variants of SCN5A
and SCN10A prevent tissue injury in inflammatory lesions through enhancement of DNA repair and
maintenance of bioenergetics. These hypotheses will be tested using multidisciplinary approaches in primary
cultures of human macrophages; macrophages, microglia, and neurons derived from human induced-
pluripotent stem cells; and in the mouse model of multiple sclerosis, experimental autoimmune
encephalomyelitis. The expectations are that we will identify novel regulator...

## Key facts

- **NIH application ID:** 10412923
- **Project number:** 5I01BX000467-11
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** MICHAEL D CARRITHERS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2010-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412923

## Citation

> US National Institutes of Health, RePORTER application 10412923, Regulation of susceptibility and severity of inflammatory diseases of the central nervous system by novel innate immune signaling pathways in human myeloid cells (5I01BX000467-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10412923. Licensed CC0.

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