Abstract
STAT3 is a master regulator of the immune responses. Here we show that M. tuberculosis-infected stat3fl/fl lysm cre mice, defective for STAT3 in myeloid cells, contained lower bacterial load in lungs and spleens, reduced granuloma extension but higher levels of pulmonary neutrophils. STAT3-deficient macrophages showed no improved control of intracellular mycobacterial growth. Instead, protection associated to elevated ability of stat3fl/fl lysm cre antigen-presenting cells (APCs) to release IL-6 and IL-23 and to stimulate IL-17 secretion by mycobacteria-specific T cells. The increased IL-17 secretion accounted for the improved control of infection since neutralization of IL-17 receptor A in stat3fl/fl lysm cre mice hampered bacterial control. APCs lacking SOCS3, which inhibits STAT3 activation via several cytokine receptors, were poor inducers of priming and of the IL-17 production by mycobacteria-specific T cells. In agreement, socs3fl/fl cd11c cre mice deficient of SOCS3 in DCs showed increased susceptibility to M. tuberculosis infection. While STAT3 in APCs hampered IL-17 responses, STAT3 in mycobacteria-specific T cells was critical for IL-17 secretion, while SOCS3 in T cells impeded IL-17 secretion. Altogether, STAT3 signalling in myeloid cells is deleterious in the control of infection with M. tuberculosis.
Highlights
Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, remains a leading public health problem worldwide
We studied the role of STAT3, a major regulator of immunity, in the control of the infection with M. tuberculosis
STAT3-deficient antigen-presenting cells (APCs) stimulated with innate receptor agonists released high levels of IL-6 and IL-23, and promoted IL-17 production by mycobacteria-specific CD4+ T cells
Summary
Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, remains a leading public health problem worldwide. Host factors determining the outcome of infection are not completely understood. A host counters mycobacterial infections primarily via TH1 immune responses that involve cellular effector mechanisms such as macrophage activation [2, 3]. The transcription factor STAT3 is a central regulator of immunity, mediating inflammatory and anti-inflammatory responses [10, 11]. STAT3 is activated by phosphorylation in response to cytokines of the IFN-receptor family (such as IL-10) and by some members of the IL-2 receptor family that uses the common γ chain receptor or after stimulation of several receptor tyrosine kinases (EGF, CSF-1, and PDGF). STAT3 is activated by the common signal transducing molecule gp130 utilized by the IL-6 receptor family [12], and in response to G-CSF and leptin as their receptors are homologous to gp130
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