Work

Pro-inflammatory and oxidative responses to burn pit relevant desert particulate matter in macrophages: A role for TLR2 signaling

Year: 2025

Type: article

Abstract: Particulate matter (PM) exposure is linked to many respiratory diseases such as asthma, yet the underlying mechanisms remain unclear. A large number of warfighters deployed to Afghanistan and Iraqi have developed deployment related respiratory disease. This study investigates the effects of burn pit-relevant desert PM from Afghanistan (APM) and comparative desert PM from China Lake, California (CPM) on oxidative stress and pro-inflammatory responses in macrophages. Using mouse monocyte cell line and primary bone marrow-derived macrophages (BMDMs) with or without Toll-like Receptor 2 (TLR2) deficiency, we assessed nitric oxide (NO . ), hydrogen peroxide (H 2 O 2 ), and cytokine production using biochemical assays, enzyme-linked immunosorbent assay (ELISA), pharmacological and genetic modulation, and bulk RNA sequencing. APM was more cytotoxic than CPM in monocytes. Both PMs increased H 2 O 2 levels, with acellular conditions generating higher H 2 O 2 levels, which was catalase-sensitive and attenuated by metal chelation. APM induced stronger NO . and cytokine C-X-C motif chemokine ligand 1 (CXCL1) responses than CPM, with NO . production attenuated by the nitric oxide synthase (NOS) inhibitor L-N G -nitroarginine methyl ester (LNAME), which also prevented cytotoxicity. TLR2 activation via agonist Pam3CSK4 enhanced NO . and CXCL1, while inhibition with antagonist C29 or TLR2 knockout partially suppressed APM-induced responses. Bulk RNA sequencing revealed that APM upregulated M1 pro-inflammatory polarization markers, many of which were significantly reduced in TLR2-deficient BMDMs. These findings demonstrate that APM exposure of monocytes/macrophages elicits stronger oxidative and pro-inflammatory responses than CPM, partially mediated through TLR2 signaling. This study provides mechanistic insight into deployment-related PM exposure and identifies potential therapeutic targets to mitigate inflammation in affected individuals. • APM is more cytotoxic and induced stronger NO . and CXCL1 responses than CPM • APM-induced NO . , was attenuated by NOS inhibition, which also reduced cytotoxicity • PMs elevated H 2 O 2 that was catalase-sensitive and was attenuated by metal chelation • TLR2 signaling mediates inflammatory responses to APM in macrophages • APM upregulates M1 polarization markers that was partially TLR2-dependent

Source: Free Radical Biology and Medicine

DOI: 10.1016/j.freeradbiomed.2025.09.035

Authors: Brian J. Day, Jie Huang, Niccolette Schaunaman, Gregory P. Downey, Hong Wei Chu

Institution: National Jewish Health

Language: English

Topic: Air Quality and Health Impacts

Subfield: Health, Toxicology and Mutagenesis

Field: Environmental Science

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,240