The NLRP3 inflammasome regulates neutrophil trafficking to HNSCC

Introduction:

There is emerging evidence that neutrophilic granulocytes (neutrophils) substantially contribute to the pathogenesis of head and neck squamous cell carcinoma (HNSCC). The underlying mechanisms, however, remain poorly understood. Recently, the NLRP3 inflammasome has been identified to play a key role for the initiation of inflammatory processes. We therefore hypothesized that this intracellular protein complex is vital for neutrophil trafficking to HNSCC.

Methods:

Employing multi-channel in vivo microscopy, neutrophil trafficking to HNSCC (cell line SCC VII) implanted into ears of C3 H mice was analyzed. Expression of adhesion and signaling molecules was evaluated by immunostaining and confocal laser scanning microscopy (tissue sections) or multi-channel flow cytometry (single cells).

Results:

Growth of HNSCC was found to be closely associated with neutrophil trafficking to these malignant tumors. Pharmacological inhibition of NLRP3 inflammasome formation almost completely abolished responses of neutrophils as well as tumor growth. In this context, neutrophils recruited by NLRP3 inflammasome activation were identified to exhibit a pro-tumorigenic ‚N2' phenotype. Mechanistically, formation of the NLRP3 inflammasome potently induced synthesis of pro-inflammatory cytokines in (peritumoral) macrophages which, in turn, activated microvascular endothelial cells, but did not directly activate neutrophils or endothelial cells, thus enabling the extravasation of neutrophils to the tumor environment.

Conclusions:

Our experimental data indicate that the NLRP3 inflammasome critically shapes the inflammatory milieu in the environment of HNSCC thereby controlling neutrophil responses and tumor growth.

Publication History

Publication Date:
18 April 2018 (online)