Neutrophils in Tuberculosis: Heterogeneity Shapes the Way?

Abstract

Infection with M. tuberculosis remains one of the most common infections in the world. The outcome of the infection depends on host ability to mount effective protection and balance inflammatory responses. Neutrophils are innate immune cells implicated in both processes. Accordingly, during M. tuberculosis infection, they play a dual role. Particularly, they contribute to the generation of effector T cells, participate in the formation of granuloma, and are directly involved in tissue necrosis, destruction, and infection dissemination. Neutrophils have a high bactericidal potential. However, data on their ability to eliminate M. tuberculosis are controversial, and the results of neutrophil depletion experiments are not uniform. Thus, the overall roles of neutrophils during M. tuberculosis infection and factors that determine these roles are not fully understood. This review analyzes data on neutrophil defensive and pathological functions during tuberculosis and considers hypotheses explaining the dualism of neutrophils during M. tuberculosis infection and tuberculosis disease.

Dynamic balance of pro‐ and anti‐inflammatory signals controls disease and limits pathology

“…During Mtb infection, neutrophils secrete both pro‐ and anti‐inflammatory cytokines. TNF, CCL2, CCL3, CCL4, CCL19, CCL20, CXCL2, CXCL9/MIG, S100A8, S100A9, all secreted by neutrophils, recruit monocytes and T lymphocytes to the infection site . Notably, the majority of the cytokines and chemokines that neutrophils secrete in turn function as neutrophil activators or attractants, resulting in a positive feedback loop .…”

“…TNF, CCL2, CCL3, CCL4, CCL19, CCL20, CXCL2, CXCL9/MIG, S100A8, S100A9, all secreted by neutrophils, recruit monocytes and T lymphocytes to the infection site . Notably, the majority of the cytokines and chemokines that neutrophils secrete in turn function as neutrophil activators or attractants, resulting in a positive feedback loop . This self‐accumulation can become detrimental if left unchecked, contributing to immune hyper‐reactivity; namely, although neutrophils do not secrete large quantities of pro‐inflammatory cytokines at the single‐cell level, the accumulated amount that a local population of neutrophils secretes can become harmful to the host.…”

“…Notably, the majority of the cytokines and chemokines that neutrophils secrete in turn function as neutrophil activators or attractants, resulting in a positive feedback loop . This self‐accumulation can become detrimental if left unchecked, contributing to immune hyper‐reactivity; namely, although neutrophils do not secrete large quantities of pro‐inflammatory cytokines at the single‐cell level, the accumulated amount that a local population of neutrophils secretes can become harmful to the host. That neutrophil death occurs through the necrosis pathway during Mtb, rather than by the anti‐inflammatory efferocytosis, and that neutrophil secretion of the anti‐inflammatory cytokines IL‐10, IL‐4, and IL‐13 is reduced, both imply that there is a positive‐feedforward neutrophilic, inflammatory response during Mtb .…”

“…TNF, CCL2, CCL3, CCL4, CCL19, CCL20, CXCL2, CXCL9/MIG, S100A8, S100A9, all secreted by neutrophils, recruit monocytes and T lymphocytes to the infection site. 49,120,121 Notably, the majority of the cytokines and chemokines that neutrophils se-…”

“…crete in turn function as neutrophil activators or attractants, resulting in a positive feedback loop 121. This self-accumulation can become detrimental if left unchecked, contributing to immune hyper-reactivity121 ; namely, although neutrophils do not secrete large quantities of pro-inflammatory cytokines at the single-cell level, the accumulated amount that a local population of neutrophils secretes can become harmful to the host.That neutrophil death occurs through the necrosis pathway during Mtb, rather than by the anti-inflammatory efferocytosis, and that neutrophil secretion of the anti-inflammatory cytokines IL-10, IL-4, and IL-13 is reduced, both imply that there is a positive-feedforward neutrophilic, inflammatory response during Mtb [121][122][123]. Through disrupting pro-inflammatory balance checkpoints in this way, infections like Mtb are thought to experience increased pathology.Easily activated, short-lived, and unable to be depleted in cynomolgus macaque models,6,49,124,125 neutrophils pose unique experimental challenges to wet lab study.…”