Abstract
Neutrophils are implicated in the pathogenesis of tuberculosis (TB), a disease caused by Mycobacterium tuberculosis infection, but the mechanisms by which they promote disease are not fully understood. Neutrophils can express cytokines that influence TB progression, and so we compared neutrophil and T-cell expression of the Th1 cytokines IFNγ and TNF, the Th2 cytokine IL-4, and regulatory cytokine IL-10 in M. tuberculosis-infected macaques to determine if neutrophil cytokine expression contributes to dysregulated immunity in TB. We found that peripheral blood neutrophils produced cytokines after stimulation by mycobacterial antigens and inactive and viable M. tuberculosis. M. tuberculosis antigen-stimulated neutrophils inhibited antigen-specific T-cell IFNγ production. In lung granulomas, neutrophil cytokine expression resembled T-cell cytokine expression, and although there was histologic evidence for neutrophil interaction with T cells, neutrophil cytokine expression was not correlated with T-cell cytokine expression or bacteria load. There was substantial overlap in the spatial arrangement of cytokine-expressing neutrophils and T cells, but IL-10-expressing neutrophils were also abundant in bacteria-rich areas between caseum and epithelioid macrophages. These results suggest that neutrophils contribute to the cytokine milieu in granulomas and may be important immunoregulatory cells in TB granulomas.
Highlights
Neutrophils are innate immune cells that play indispensable roles in protection against microbial infection
Neutrophils accumulated at the interface between epithelioid macrophages and caseous necrosis, an area that can harbor substantial numbers of M. tuberculosis bacilli,[1] and cells in this region often had degenerative phenotypes associated with cells undergoing necrosis or apoptosis
To assess whether cytokine expression differs by DISCUSSION Neutrophils are implicated in the pathogenesis of TB, but important aspects of their biology, including how they interact with other cells in granulomas to promote disease, remain unknown
Summary
Neutrophils are innate immune cells that play indispensable roles in protection against microbial infection. Neutrophils are often found in the granulomas,[1] the multicellular lesions caused by Mycobacterium tuberculosis infection, the contributions of neutrophils to immunity in tuberculosis (TB) are complex and controversial.[2] Work done in zebrafish[3] and rhesus macaques[4] suggests neutrophils may be protective during acute infection and studies in humans have identified an inverse correlation between peripheral blood neutrophil numbers and disease risk.[5] The same study demonstrated that neutrophilexpressed antimicrobial peptides can kill M. tuberculosis[5] but studies on postacute TB in mice,[6,7] macaques,[8,9] and humans[10,11,12,13] suggest that neutrophilic inflammation correlates with increasingly severe disease and higher bacteria numbers The basis for this relationship is unclear, but neutrophils may promote mycobacterial persistence by serving as a nutrient reservoir for M. tuberculosis[6] or providing a short-term replicative niche.[14] Less is known about what neutrophils do while they are in granulomas or if they contribute to the regulatory milieu in tuberculous granulomas
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