# Selective JAK2 inhibition by TG101209 reprograms macrophage polarization and alleviates acute lung injury

## TL;DR

This study shows that the JAK2 inhibitor TG101209 reduces lung inflammation and improves recovery in acute lung injury by shifting immune cells to a healing state.

## Contribution

TG101209 is shown to reprogram macrophage polarization via JAK2/STAT3 inhibition, offering a novel therapeutic strategy for ALI.

## Key findings

- TG101209 reduced pulmonary inflammation and improved lung function in ALI models.
- The drug inhibited M1 macrophage polarization and promoted M2 polarization by modulating JAK2/STAT3 signaling.
- TG101209 decreased phosphorylation of JAK2 and STAT3, confirming its mechanism of action.

## Abstract

Acute lung injury (ALI) represents a critical respiratory syndrome involving extensive alveolar injury and uncontrolled inflammation, yet it continues to exhibit high mortality rates in the absence of effective treatments. Here we evaluate TG101209, a selective Janus kinase 2 (JAK2) inhibitor, as a modulator of macrophage polarization and a candidate intervention for ALI.

This study employed both in vivo and in vitro models to investigate the protective effects of TG101209 against ALI. Using lipopolysaccharide (LPS)-induced ALI mice and RAW264.7 inflammatory injury models, the JAK2/STAT3 signaling axis was validated by western blotting and immunofluorescence.

TG101209 alleviated pulmonary inflammation, improved lung function, inhibited M1 polarization, and promoted M2 polarization. Specifically, TG101209 downregulated CD80 and iNOS while upregulating CD163 and Arg1 at both mRNA and protein levels. TG101209 treatment markedly decreased the phosphorylation levels of JAK2 and STAT3 at Ser727 and Tyr705.

TG101209 promotes macrophage polarization toward the M2 phenotype by blocking JAK2/STAT3 activation, indicating its therapeutic value in ALI.