Activation of the Adipose Tissue NLRP3 Inflammasome Pathway in Cancer Cachexia

• Published in: Frontiers in immunology Vol. 12; p. 729182
• Main Authors: de Jesus, Joyce de Cassia Rosa, Murari, Ariene Soares de Pinho, Radloff, Katrin, de Moraes, Ruan Carlos Macêdo, Figuerêdo, Raquel Galvão, Pessoa, Ana Flavia Marçal, Rosa-Neto, José César, Matos-Neto, Emídio Marques, Alcântara, Paulo S M, Tokeshi, Flavio, Maximiano, Linda Ferreira, Bin, Fang Chia, Formiga, Fernanda Bellotti, Otoch, José P, Seelaender, Marilia
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 23-09-2021
• Subjects: adipose tissue heterogeneity; Adult; Aged; cachexia; Cachexia - etiology; Cachexia - genetics; Cachexia - metabolism; Cachexia - pathology; Caspase 1 - genetics; Caspase 1 - metabolism; Colorectal Neoplasms - complications; Female; Humans; Immunology; Inflammasomes - genetics; Inflammasomes - metabolism; inflammation; Interleukin-18 - genetics; Interleukin-18 - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Intra-Abdominal Fat - metabolism; Intra-Abdominal Fat - pathology; Male; Middle Aged; neoplasms; NF-kappa B - genetics; NF-kappa B - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Signal Transduction; Subcutaneous Fat - metabolism; Subcutaneous Fat - pathology; Tissue Culture Techniques; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; adipose tissue heterogeneity; NLRP3 inflammasome; neoplasms; inflammation; cachexia
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.729182

Cachexia is a paraneoplastic syndrome that accompanies and compromises cancer treatment, especially in advanced stages, affecting the metabolism and function of several organs. The adipose tissue is the first to respond to the presence of the tumor, contributing to the secretion of factors which drive the systemic inflammation, a hallmark of the syndrome. While inflammation is a defensive innate response, the control mechanisms have been reported to be disrupted in cachexia. On the other hand, little is known about the role of NLRP3 inflammasome in this scenario, a multiprotein complex involved in caspase-1 activation and the processing of the cytokines IL-1β and IL-18.
based on the evidence from our previous study with a rodent model of cachexia, we examined the activation of the NLRP3 inflammasome pathway in two adipose tissue depots obtained from patients with colorectal cancer and compared with that another inflammatory pathway, NF-κB.
For CC we found opposite modulation in ScAT and PtAT for the gene expression of TLR4, Caspase-1 (cachectic group) and for NF-κB p50, NF-κB p65, IL-1β. CD36, expression was decreased in both depots while that of NLRP3 and IL-18 was higher in both tissues, as compared with controls and weight stable patients (WSC). Caspase-1 basal protein levels in the ScAT culture supernatant were higher in WSC and (weight stable patients) CC, when compared to controls. Basal ScAT explant culture medium IL-1β and IL-18 protein content in ScAT supernatant was decreased in the WSC and CC as compared to CTL explants.
The results demonstrate heterogeneous responses in the activation of genes of the NLRP3 inflammasome pathway in the adipose tissue of patients with cancer cachexia, rendering this pathway a potential target for therapy aiming at decreasing chronic inflammation in cancer.