# HSPA1A Can Alleviate CFA-Induced Inflammatory Pain by Modulating Macrophages

## TL;DR

This study shows that HSPA1A can reduce inflammatory pain by changing how macrophages function, offering a new approach for pain treatment.

## Contribution

The study reveals a novel mechanism by which HSPA1A alleviates inflammatory pain through macrophage modulation and metabolic reprogramming.

## Key findings

- HSPA1A reduces CFA-induced mechanical allodynia, independent of T/B cells and neutrophils.
- HSPA1A suppresses M1 macrophage polarization and pro-inflammatory cytokine expression.
- Macrophage metabolism shifts from glycolysis to oxidative phosphorylation with HSPA1A treatment.

## Abstract

Current clinical approaches for managing inflammatory pain are frequently accompanied by adverse effects, significantly compromising patients’ quality of life. This study investigates the analgesic potential of Heat Shock Protein Family A Member 1A (HSPA1A) in alleviating Complete Freund’s Adjuvant (CFA)-induced inflammatory pain. The immunomodulatory mechanisms were elucidated through behavioral studies, flow cytometry, transcriptomics, proteomics, and cellular metabolic analyses. Findings indicate that HSPA1A mitigates CFA-induced mechanical allodynia, an effect independent of T or B lymphocytes and neutrophils but positively correlated with macrophage abundance. Transcriptomic RNA sequencing suggests involvement of inflammation-associated pathways. In vitro experiments demonstrate that HSPA1A suppresses the polarization of bone marrow-derived macrophages toward the pro-inflammatory M1 phenotype in an inflammatory model, with decreased mRNA expression of pro-inflammatory cytokines Interleukin-1β (Il1b) and Tumor Necrosis Factor (TNF). Macrophage metabolism undergoes reprogramming, characterized by reduced glycolysis and enhanced oxidative phosphorylation. Proteomic pathway analysis reveals suppression of pro-inflammatory and glycolytic proteins, coupled with upregulation of anti-inflammatory and tricarboxylic acid cycle-related proteins. In summary, HSPA1A likely exerts its analgesic effects by inhibiting glycolysis in macrophages, providing novel insights into inflammatory pain management and highlighting potential therapeutic targets for future clinical drug development with substantial translational potential.