Abstract
The intestinal mucosal barrier is critical for host defense against pathogens infection. Here, we demonstrate that the mixed lineage kinase-like protein (MLKL), a necroptosis effector, promotes intestinal epithelial barrier function by enhancing inflammasome activation. MLKL−/− mice were more susceptible to Salmonella infection compared with wild-type counterparts, with higher mortality rates, increased body weight loss, exacerbated intestinal inflammation, more bacterial colonization, and severe epithelial barrier disruption. MLKL deficiency promoted early epithelial colonization of Salmonella prior to developing apparent intestinal pathology. Active MLKL was predominantly expressed in crypt epithelial cells, and experiments using bone marrow chimeras found that the protective effects of MLKL were dependent on its expression in non-hematopoietic cells. Intestinal mucosa of MLKL−/− mice had impaired caspase-1 and gasdermin D cleavages and decreased interleukin (IL)-18 release. Moreover, administration of exogenous recombinant IL-18 rescued the phenotype of increased bacterial colonization in MLKL−/− mice. Thus, our results uncover the role of MLKL in enhancing inflammasome activation in intestinal epithelial cells to inhibit early bacterial colonization.
Highlights
The gastrointestinal (GI) tract of mammals is colonized by tens of trillions of microorganisms, which are primarily composed of bacteria, viruses, fungi, parasites, and archaea, and is constantly exposed to a wide array of these microbial antigens, requiring the mucosal immune system to induce tolerance to the commensal microbes while still mounting potent responses to pathogens [1, 2]
To determine the biological role of mixed lineage kinase-like protein (MLKL) in Salmonella infection in vivo, streptomycin-pretreated WT and MLKL−/− mice were orally administrated with 1 × 108 colony-forming unit (CFU) of Salmonella enterica subsp. enterica serovar Typhimurium SL1344 (Salmonella strain SL1344), and the mortality of mice were monitored over 15 days
Based on the above results, we speculated that increased pathology in MLKL−/− mice during Salmonella infection might link to increased colonization levels
Summary
The gastrointestinal (GI) tract of mammals is colonized by tens of trillions of microorganisms, which are primarily composed of bacteria, viruses, fungi, parasites, and archaea, and is constantly exposed to a wide array of these microbial antigens, requiring the mucosal immune system to induce tolerance to the commensal microbes while still mounting potent responses to pathogens [1, 2]. When Salmonella first enters the host it initially propagates inside the GI tract and overcomes colonization resistance provided by the gut Abbreviations: MLKL, mixed lineage kinase-like protein; GSDMD, gasdermin D; Salmonella, Salmonella enterica serovar typhimurium; MLNs, mesenteric lymph nodes; IECs, intestinal epithelial cells; PRR, pattern recognition receptors; TLRs, tolllike receptors; RIPK1, receptor interacting protein kinase 1; RIPK3, receptor interacting protein kinase 3; CFU, colony-forming unit; H&E, hematoxylin and eosin; PMN, polymorphonuclear leukocyte; ZO-1, zonula occludens-1; rIL-18, recombinant IL-18. To gain access to the host, it must breach the intestinal epithelial barrier [7, 8] and translocate and/or replicate outside the gut, such as the mesenteric lymph nodes (MLNs), spleen, and liver, causing a severe inflammation of the intestinal mucosal epithelium, resulting gastroenteritis in humans, and typhoid-like systemic illness in mice [9]
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