Activation of pulmonary invariant NKT cells leads to exacerbation of acute lung injury caused by LPS through local production of IFN-  and TNF-  by Gr-1+ monocytes

Abstract

Invariant NK T (iNKT) cells are known to play a critical role in the regulation of inflammatory responses in various clinical settings. In the present study, we assessed the contribution of iNKT cells to the development of acute lung injury (ALI), which was caused by intra-tracheal administration of LPS. Jα18 gene-disrupted mice lacking these cells underwent neutrophilic inflammatory responses in lungs at an equivalent level as control mice. Next, mice were sensitized intra-tracheally with α-galactosylceramide, an activator of iNKT cells, followed by challenge with LPS. In this model, mice showed severe lung injury, and all mice were killed within 72 h after LPS injection. IFN-γ and tumor necrosis factor (TNF)-α were strikingly elevated in the lungs of these mice. Administration of neutralizing mAb against IFN-γ and TNF-α attenuated lung injury in a histopathological analysis and improved their survival rate. Flow cytometric analysis revealed that IFN-γ was expressed in NK cells, iNKT cells and also Gr-1(dull+)Ly-6C(+) monocytes and TNF-α was detected mainly in Gr-1(bright+)Ly-6G(+) neutrophils and Gr-1(dull+)Ly-6C(+) monocytes. Otherwise, in mice treated with LPS alone, IFN-γ was not detected in the lungs and Gr-1(bright+)Ly-6G(+) neutrophil was a main cellular source of TNF-α production. Anti-Gr-1 mAb resulted in the attenuation of ALI and decrease in the level of these cytokines. These results indicated that activation of iNKT cells led to striking exacerbation of ALI caused by LPS and that Gr-1(+) monocytes were recruited in the lungs with expressing IFN-γ and TNF-α and played an important role in the development of these responses.

Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice

“…Then, iNKT cells rapidly proliferate and increase to the peak level 72 hr after αGC administration. The activation of iNKT cells by αGC has been observed in various organs, such as spleen, liver, lung, and kidney [18,19,[27][28][29].…”

Effect of invariant natural killer T cells with IL-5 and activated IL-6 receptor in ventilator-associated lung injury in mice

“…While the percentage of lymphocytes remained essentially unchanged in the BALF following ventilation, as described above, iNKT cells have recently been reported to be involved in the pathogenesis of severe pneumonia and inflammatory lung damage [21,26]. To further elucidate the involvement of lymphocytes in the VALI in our model, we examined the roles of iNKT cells in the onset of VALI by determining the counts of these cells in the lung tissue in the animal models of VALI by FCM ( Figure 1A-C).…”

“…The iNKT cells, occurring as a small proportion, are known to be critical for the induction of innate immunity against a variety of pathogens. They are well known to promote occurrence of ALI via inducing the production of IFN-γ [26,27,[39][40][41]. Aoyagi et al [26] have demonstrated that IFN-γ produced by activated iNKT cells leads to severe lung injury and it improves by IFN-γ antibody administration in LPS-induced ALI.…”

“…Recently, naturally occurring invariant natural killer T (iNKT) cells, which express an invariant T cell receptor (TCR) encoded by the Vα14 and Jα28 segments, have been reported to be involved in airway inflammation and injury mediated by proinflammatory cytokines [17][18][19][20][21]. Actually, iNKT cells have been shown to induce antitumor, allergic, and autoimmune responses [22][23][24][25], as well as facilitate ARDS caused by lipopolysaccharide [26,27].…”

The Role of CD1d-Restricted NKT Cells in the Clearance of Pseudomonas aeruginosa from the Lung Is Dependent on the Host Genetic Background

“…NKT cells can be activated directly, through the recognition of glycolipids presented by CD1d (6), or indirectly, through interleukin-12 (IL-12)) and IL-18 produced upon recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (7). Once activated, NKT cells can rapidly produce large amounts of a wide variety of cytokines and chemokines which have significant modulatory effects during the early stages of infection on the function of leukocytes of both the innate and adaptive arms of the immune system, including neutrophils and macrophages (8)(9)(10). Previous investigations into the role of NKT cells in the host response to P. aeruginosa infection of the lungs have yielded conflicting results, with one report demonstrating that NKT cells were critical in mediating clearance of lung P. aeruginosa (11), while another found little evidence of a role for NKT cells (12).…”