bims-inflin 2024-10-20 papers

Immunol Rev. 2024 Oct 15.

Inflammasome-mediated pyroptosis in defense against pathogenic bacteria.

Changhoon Oh, Todd J Spears, Youssef Aachoui.

Macrophages, neutrophils, and epithelial cells are pivotal components of the host's immune response against bacterial infections. These cells employ inflammasomes to detect various microbial stimuli during infection, triggering an inflammatory response aimed at eradicating the pathogens. Among these inflammatory responses, pyroptosis, a lytic form of cell death, plays a crucial role in eliminating replicating bacteria and recruiting immune cells to combat the invading pathogen. The immunological function of pyroptosis varies across macrophages, neutrophils, and epithelial cells, aligning with their specific roles within the innate immune system. This review centers on elucidating the role of pyroptosis in resisting gram-negative bacterial infections, with a particular focus on the mechanisms at play in macrophages, neutrophils, and intestinal epithelial cells. Additionally, we underscore the cell type-specific roles of pyroptosis in vivo in these contexts during defense.

Keywords: inflammasome; intestinal epithelial cells; macrophage; neutrophil; pyroptosis

DOI: https://doi.org/10.1111/imr.13408

Immunol Rev. 2024 Oct 17.

Regulation of the NLRP3 inflammasome by autophagy and mitophagy.

Suman Gupta, Suzanne L Cassel, Fayyaz S Sutterwala, Jargalsaikhan Dagvadorj.

The NLRP3 inflammasome is a multiprotein complex that upon activation by the innate immune system drives a broad inflammatory response. The primary initial mediators of this response are pro-IL-1β and pro-IL-18, both of which are in an inactive form. Formation and activation of the NLRP3 inflammasome activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 and triggers the formation of gasdermin D pores. Gasdermin D pores allow for the secretion of active IL-1β and IL-18 initiating the organism-wide inflammatory response. The NLRP3 inflammasome response can be beneficial to the host; however, if the NLRP3 inflammasome is inappropriately activated it can lead to significant pathology. While the primary components of the NLRP3 inflammasome are known, the precise details of assembly and activation are less well defined and conflicting. Here, we discuss several of the proposed pathways of activation of the NLRP3 inflammasome. We examine the role of subcellular localization and the reciprocal regulation of the NLRP3 inflammasome by autophagy. We focus on the roles of mitochondria and mitophagy in activating and regulating the NLRP3 inflammasome. Finally, we detail the impact of pathologic NLRP3 responses in the development and manifestations of pulmonary disease.

Keywords: NLRP3; caspase‐1; inflammasome; lung injury; mitochondria

DOI: https://doi.org/10.1111/imr.13410

Microb Pathog. 2024 Oct 11. pii: S0882-4010(24)00481-9. [Epub ahead of print] 107014

Ferroptosis: A new way to intervene in the game between Mycobacterium tuberculosis and macrophages.

Wuerken Jumabayi, Abdusemer Reyimu, Rongrong Zheng, Pawuziye Paerhati, Mamatali Rahman, Xiaoguang Zou, Aimin Xu.

Mycobacterium tuberculosis (Mtb), the main pathogen responsible for the high mortality and morbidity of tuberculosis (TB) worldwide, primarily targets and invades macrophages. Infected macrophages activate a series of immune mechanisms to clear Mtb, however, Mtb evades host immune surveillance through subtle immune escape strategies to create a microenvironment conducive to its own proliferation, growth, and dissemination, while inducing immune cell death. The course of TB is strongly correlated with the form of cell death, including apoptosis, pyroptosis, and necrosis. Recent studies have revealed that ferroptosis, a novel type of programmed cell death characterized by iron-dependent lipid peroxidation, is closely linked to the regulatory mechanisms of TB. The central role of ferroptosis in the pathologic process of TB is increasingly becoming a focal point for exploring new therapeutic targets in this field. This paper will delve into the dynamic game between Mtb and host immune cells, especially the role of ferroptosis in the pathogenesis of TB. At the same time, this paper will analyze the regulatory pathways of ferroptosis and provide unique insights and innovative perspectives for TB therapeutic strategies based on the ferroptosis mechanism. This study not only expands the theoretical basis of TB treatment, but also points out the direction of future drug development, providing new possibilities for overcoming this global health problem.

Keywords: Ferroptosis; Lipid Peroxidation; Macrophages; Mycobacterium tuberculosis; Tuberculosis

DOI: https://doi.org/10.1016/j.micpath.2024.107014

J Innate Immun. 2024 Oct 15. 1-23

TLR2 and NLRP3 Orchestrate Regulatory Roles in Escherichia coli Infection-Induced Septicemia in Mouse Models.

Zhiguo Gong, Wei Mao, Jiamin Zhao, Peipei Ren, Zhuoya Yu, Yunjie Bai, Chao Wang, Yuze Liu, Shuang Feng, Surong Hasi.

Introduction Escherichia coli (E. coli) is a significant commensal gram-negative bacterium that can give rise to various diseases. The roles of Toll-like receptor 2 (TLR2) and the NLR pyrin domain-containing 3 (NLRP3) inflammasome in sepsis induced by E. coli infection remain unclear. Methods In vivo, we investigated differences in mortality, production of inflammatory mediators, organ damage, neutrophil count, and bacterial load during E. coli infection in C57BL/6J mice, as well as in mice deficient in TLR2 or NLRP3. In vitro, we investigated the impact of E. coli on the activation of TLR2 and NLRP3 in macrophages and the influence of TLR2 and NLRP3 on the activation of inflammatory signaling pathways and the secretion of inflammatory mediators in macrophages induced by E. coli infection. Results TLR2-deficient (TLR2-/-) and NLRP3-deficient (NLRP3-/-) mice exhibit significantly increased mortality and organ damage after E. coli infection. These mice also show elevated levels of TNF-α and IL-10 in serum and peritoneal lavage fluid (PLF). Additionally, TLR2-/- and NLRP3-/- mice display heightened neutrophil recruitment, increased bacterial load in the blood. Furthermore, macrophages from these mice demonstrate a significant reduction in the activation of the MAPK signaling pathway. Conclusion TLR2 and NLRP3 play crucial roles in modulating inflammatory mediator expression, immune cell recruitment, and bactericidal activity, thereby preventing excessive tissue damage and reducing mortality in E. coli-induced sepsis.

DOI: https://doi.org/10.1159/000541819

Nat Commun. 2024 Oct 17. 15(1): 8965

Tissue niche influences immune and metabolic profiles to Staphylococcus aureus biofilm infection.

Zachary Van Roy, Prabakar Arumugam, Blake P Bertrand, Dhananjay D Shinde, Vinai C Thomas, Tammy Kielian.

Infection is a devastating post-surgical complication, often requiring additional procedures and prolonged antibiotic therapy. This is especially relevant for craniotomy and prosthetic joint infections (PJI), both of which are characterized by biofilm formation on the bone or implant surface, respectively, with S. aureus representing a primary cause. The local tissue microenvironment likely has profound effects on immune attributes that can influence treatment efficacy, which becomes critical to consider when developing therapeutics for biofilm infections. However, the extent to which distinct tissue niches influence immune function during biofilm development remains relatively unknown. To address this, we compare the metabolomic, transcriptomic, and functional attributes of leukocytes in mouse models of S. aureus craniotomy and PJI complemented with patient samples from both infection modalities, which reveals profound tissue niche-dependent differences in nucleic acid, amino acid, and lipid metabolism with links to immune modulation. These signatures are both spatially and temporally distinct, differing not only between infection sites but evolving over time within a single model. Collectively, this demonstrates that biofilms elicit unique immune and metabolic responses that are heavily influenced by the local tissue microenvironment, which will likely have important implications when designing therapeutic approaches targeting these infections.

DOI: https://doi.org/10.1038/s41467-024-53353-8