# Insufficient CXCL13 secretion in leprosy foamy macrophages attenuates lymphocyte recruitment and antimicrobial protein production

## TL;DR

This study shows that low CXCL13 in leprosy-related foamy macrophages weakens immune responses and antimicrobial defenses.

## Contribution

The study identifies the NLRP12/NF-κB/CXCL13 axis as a key regulator in immune evasion by mycobacteria in foamy macrophages.

## Key findings

- CXCL13 is upregulated in infected macrophages but suppressed in foamy macrophages via NLRP12.
- CXCL13 promotes lymphocyte migration and antimicrobial protein secretion when applied in vitro.
- NLRP12 inhibits p52 expression, reducing CXCL13 in foamy macrophages during infection.

## Abstract

Pathogens trigger metabolic reprogramming, leading to the formation of foamy macrophages (FMs). This process provides a favorable environment for bacterial proliferation and enables bacteria to evade immune killing.

To elucidate the mechanisms by which pathogens escape immune surveillance and elimination via the formation of FMs.

We constructed a FM model using monocyte-derived macrophages (MDMs) that were incubated with oxidized low-density lipoprotein (oxLDL). Subsequently, we employed bulk RNA-sequencing (bulk RNA-seq) to comprehensively analyze the immune responses in MDMs and FMs against Mycobacterium leprae (M. leprae) infection in samples from 10 healthy individuals.

We found that CXCL13, a component of the cytokine-cytokine receptor interaction pathway, was specifically upregulated in M. leprae infected MDMs, when compared with M. leprae infected FMs. Significantly, further functional analyses revealed that in vitro treatment with CXCL13 could enhance the expression of CXCR5, thereby promoting lymphocyte migration and secretion of antimicrobial proteins. Additionally, NLRP12 was found to be specifically and highly expressed in the NOD-like receptor signaling pathway, which was enriched in infected FMs. In macrophages, M. leprae infection increased CXCL13 expression via NF-κB signal pathway. Conversely, in FMs, mycobacteria induced upregulation of CXCL13 was suppressed by NLRP12 through the inhibition of p52 factor expression.

In conclusion, the NLRP12/NF-κB/CXCL13 axis is crucial for the immune response of FMs after mycobacterial infection. These findings contribute to a deeper understanding of the pathological mechanisms of mycobacterial infection.