Antimicrobial therapy combined with C-C chemokine receptor type 2 modulation dampens mycobacteria-aggravated monocyte activation and atherosclerosis.

BACKGROUND

Tuberculosis is associated with increased risk of cardiovascular events. We investigated the impact of antimicrobial therapy alone and in combination with anti-CCR2 modulation in monocyte profiling and atherosclerosis development.

METHODS

Twelve-week-old low-density lipoprotein receptor knockout (Ldlr -/-) mice were infected with Mycobacterium bovis Bacille-Calmette-Guérin (BCG; 1.0-2.5 × 106 colony-forming units) via the intranasal route and fed a western-type high-fat diet for 16 weeks. Mice were treated with oral isoniazid and rifampin (INH/RIF) between weeks 4 and 12 to induce microbiologic clearance, with and without intraperitoneal injections of anti-CCR2 monoclonal antibodies administered twice weekly. Age-matched infected and uninfected Ldlr -/- mice served as controls. We assessed monocyte phenotyping using flow cytometry, and quantified atherosclerosis in aortas using Oil-Red-O staining. Plaque composition was assessed in aortic roots.

RESULTS

Compared to uninfected mice, untreated BCG-infected mice and BCG-infected mice treated with INH/RIF exhibited an expansion of Ly6Clow non-classical monocytes, as well as increased expression of monocyte activation markers. BCG-infected mice developed increased atherosclerotic lesions in their aortae, regardless of INH/RIF treatment. The addition of anti-CCR2 adjunctive therapy to INH/RIF treatment decreased monocyte activation markers including MHC-II, CD64, CD36, CX3CR1, and diminished interleukin-6 production upon lipopolysaccharide stimulation. Finally, anti-CCR2 adjunctive therapy decreased atherosclerosis lesions of BCG-infected INH/RIF-treated mice, while also decreasing plaque size and lipid content.

CONCLUSIONS

Monocyte activation and atherosclerosis burden remained elevated after BCG clearance with antimicrobials. The addition of anti-CCR2 to antimicrobial therapy dampened monocyte activation and atherosclerosis development. Our results indicate that combining antimicrobials with CCR2 immunomodulation may reduce mycobacteria-aggravated atherosclerosis.