Identification of novel innate immune mechanisms regulating oesophageal adenocarcinoma (OAC) progression and bacterial infection

Abstract

Inflammation is an essential immune system response to pathogens, damaged cells and stress stimuli and has an essential role in tissue repair and regeneration. The inflammatory response is the coordinated activation of signalling pathway leading to immune cell recruitment into the site of infection and production of inflammatory mediators. In response to the recognition of microorganisms and sterile stressors, a multiprotein complex, called the inflammasome is formed. The inflammasome activates the highly pro-inflammatory cytokines IL-1β and IL-18 and induced programmed cell death-pyroptosis thus inducing inflammation. Despite the undeniable protective role of inflammation, increasing evidence shows that that deregulation in immune response or prolonged inflammation causes and advances many common diseases. Chronic inflammation plays a very important role in oesophageal adenocarcinoma (OAC) and its only known precursor, Barrett’s oesophagus (BO). Recent studies suggest that microbial dysbiosis in oesophagus could contribute to BO and increase the risk of OAC development. TLR2 is involved in the innate immune response to microbial pathogens and host-derived molecules.We assume that TLR2 upregulation will increase the sensitivity of oesophageal cells to bacteria thus leading to chronic inflammation. We show that BO and early-stage OAC cells were responsive to TLR2 stimulation and TLR2 neutralising antibody successfully inhibits TLR2-mediated chemokine production. Factors secreted from TLR2-activated oesophageal cells induce TLR2-mediated differentiation of murine macrophages into M2-like/TAM phenotype. We identify High Mobility Group Box 1 protein (HMGB1) as one of the factors secreted from TLR2-stimulated oesophageal adenocarcinoma cells. We show that extracellular HMGB1 can efficiently prime macrophages for inflammasome activation, upregulating caspase-11 and IL-1B. Findings suggest that HMGB1 is a potential target for early-stage OAC, and that blocking TLR2 signalling may limit HMGB1 release, inflammatory cell infiltration and inflammation during OAC progression. Inflammation is critical for tuberculosis (TB) pathogenesis. Numerous host innate immune responses are induced upon M.tuberculosis (Mtb), although their mechanisms and impact on mycobacterium are not well understood. It is estimated that about one-third of the global population is infected with Mtb. When the infection is not cleared it remains in a latent form for a long time and only 5-10% of infected individuals will develop active disease at some stage of their life. The inhibition of inflammation is the main survival strategy of Mtb. Nitric oxide and IL-1β play an important role in the host resistance to Mtb. Here we investigated the role of caspase-11 in Mtb infection. We first show that STAT1 activation, nitric oxide production and IL-1β expression in macrophages is mediated by caspase-11. The iNOS-induced nitric oxide production is regulated through IFNAR/JAK/STAT1 pathway. We also determined that Caspase-11 is required for restriction of Mtb proliferation in murine macrophages. As nitric oxide is well known to confine the growth of Mtb we hypothesise that Mtb-induced caspase-11 increases iNOS expression and nitric oxide production and is a crucial protein in the innate immune response to TB-induced pathogen. Inhibition of caspase-11 by mycobacteria could be a potential mechanism allowing Mtb proliferation in the host. Peptic ulcers are another example of the inflammation-related condition, caused by the interaction between bacterial and host factors and are often influenced by the presence of Helicobacter pylori infection or use of NSAIDs. This study demonstrates enhanced expression of caspase-4 in peptic ulcer patient biopsies, indicating that pyroptosis and non-canonical inflammasome activity may be processes involved in peptic ulcer disease. We show that primary murine macrophages infected with H. pylori upregulate caspase-11 (the orthologue of human caspase-4), activate caspase-1 and secrete IL-1β. Prostaglandin E2 inhibits caspase-4 mediated and indirectly caspase-1 driven pyroptosis probably through the limitation of DAMPs production. Overall, evidence is provided for a pathological role of caspase-4/11 in peptic ulcer disease and proposes that targeting caspase-4 or inhibiting pyroptosis may have therapeutic potential in the management of peptic ulcers.